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HGF (hepatocyte growth factor (hepapoietin A; scatter factor))

Written2011-06Gagani Athauda, Fabiola Cecchi, Tim Ito, Alessio Giubellino, Daniel Rabe, Kristen Raffensperger, Young Lee, Donald P Bottaro
Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, USA (GA); Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA (GA, FC, TI, AG, DR, KR, YL, DPB)

(Note : for Links provided by Atlas : click)


Alias (NCBI)DFNB39
HGNC Alias symbSF
HGNC Alias namehepatopoietin A
 fibroblast-derived tumor cytotoxic factor
 scatter factor
 lung fibroblast-derived mitogen
HGNC Previous nameDFNB39
HGNC Previous namedeafness, autosomal recessive 39
 hepatocyte growth factor (hepapoietin A; scatter factor)
LocusID (NCBI) 3082
Atlas_Id 385
Location 7q21.11  [Link to chromosome band 7q21]
Location_base_pair Starts at 81750900 and ends at 81770047 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping HGF.png]
Local_order 5'- 81237388 - 81169380 -3'; strand: (-). The human HGF gene is centromeric to CACNA2D1 (calcium channel, voltage-dependent, alpha 2/delta subunit 1) and telomeric to LOC100128317 (similar to hCG2036731) and SEMA3C (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3C).
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
HFM1 (1p22.2)::HGF (7q21.11)RSBN1L (7q11.23)::HGF (7q21.11)


Description Total length: 68009 bases; mRNA product length: 2820, processed length: 2805.
Transcription The HGF gene structure consists of 18 exons and 16 introns spanning 68 Mb. Five human mRNA transcript variants arise from alternative splicing. Transcript variant 1 (NCBI Accession NM_000601) encodes the longest isoform (isoform 1; NP_000592) comprised of 728 amino acids. Transcript variant 2 (NM_001010931) lacks multiple 3' exons but includes an alternate 3' exon relative to variant 1. The encoded protein (isoform 2; NP_001010931) is truncated after the second kringle domain, contains 290 amino acids and has a distinct carboxyl-terminus relative to isoform 1. Transcript variant 3 (NM_001010932) lacks an in-frame coding segment present in isoform 1. The encoded protein isoform 3 contains 723 amino acids but lacks the sequence "FLPSS" at positions 162-166 within the first kringle domain of isoform 1. Transcript variant 4 (NM_001010933) combines the 3' truncation of variant 2 and internal deletion of isoform 3. The encoded protein (isoform 4; NP_001010933) contains 285 amino acids and is identical to isoform 2 except it lacks the sequence "FLPSS" present at positions 162-166 in isoforms 1 and 2. Transcript variant 5 (NM_001010934) lacks multiple 3' exons and has an alternate 3' segment that is distinct from either isoform 1 or 2. The encoded protein isoform 5 (NP_001010934) contains 210 amino acids with a unique carboxyl terminal sequence immediately following kringle 1.
Pseudogene There are no known pseudogenes.


  A schematic representation of the domain structure of pre-pro-HGF protein isoform 1 (728 amino acids total), which consists of a signal peptide for secretion (residues 1-31), an amino-terminal heparin binding domain (N), 4 kringle domains, and a serine protease-like domain. Gray areas between named domains represent structurally undefined regions. The lengths of all regions are directly proportional to their sequence length.
Description The human HGF gene encodes full-length HGF and two truncated isoforms (NK1 and NK2) which consist of the amino-terminal domain (N) linked in tandem with the first one (K1) or two (K1+K2) kringle domains, respectively. All three isoforms bind to the receptor tyrosine kinase Met (Bottaro et al., 1991; Chan et al., 1991; Lokker et al., 1992; Cioce et al., 1996); like full-length HGF, NK1 stimulates mitogenesis, motogenesis and morphogenesis, though at reduced potency and with greater HS dependence, suggesting that the primary Met binding site is contained within this fragment (Montesano et al., 1998; Stahl et al., 1997). NK2 can competitively antagonize mitogenicity stimulated by HGF or NK1, but retains motogenic activity, activating the Met kinase and a subset of those intracellular signaling pathways activated by either HGF or NK1 (Day et al., 1999). Within NK1, the N domain contains the HS binding site (as described in detail below) and K1 contains the primary site of Met interaction (Lokker et al., 1993; Rubin et al., 2001).
All HGF isoforms are synthesized as pre-pro-peptides that undergo proteolytic cleavage at or near residue 31 prior to secretion as pro-HGF. Full-length single chain pro-HGF (isoforms 1 and 3) undergo proteolytic cleavage at R494-V495 to become biologically active heterodimers consisting of a ~69 kDa alpha (or heavy) chain disulfide-linked to a ~34 kDa beta (or light) chain; this conversion is essential for biological activity (Miyazawa et al., 1989; Nakamura et al., 1989; Gak et al., 1992; Hartmann et al., 1992; Lokker et al., 1992; Naka et al., 1992; Naldini et al., 1992). Several serine proteases are capable of HGF activation in vitro, including HGF activator (HGFA) (Shimomura et al., 1992; Miyazawa et al., 1993; Shimomura et al., 1995; Shimomura et al., 1997), matriptase (Lee et al., 2000), hepsin (Herter et al., 2005; Kirchhofer et al., 2005), certain plasminogen activator family members (Mars et al., 1993; Mars et al., 1995; Mars et al., 1996), and blood factors XIa and XIIa (Miyazawa et al., 1993; Shimomura et al., 1995; Peek et al., 2002). Conversion from single chain to 2-chain HGF is further regulated by the Kunitz-type inhibitors HGF activator inhibitor-1 (HAI-1), HAI-1B (a splice variant of HAI-1) and HAI-2 (Kawaguchi et al., 1997; Kataoka et al., 2000b; Delaria et al., 1997; Denda et al., 2002; Kirchhofer et al., 2003; Shia et al., 2005; Eigenbrot et al., 2010). The truncated HGF isoforms (2, 4 and 5) do not contain R494 and do not require this processing step for biological activity, which are generally less potent and/or less pleiotropic than that of the full-length HGF isoforms (Stahl et al., 1997; Montesano et al., 1998).
The interaction between HGF and heparan sulfate (HS) proteoglycans is also profoundly relevant to HGF biology. HGF was shown to be bound to the extracellular matrix of normal adult rat liver isolates (Masumoto and Yamamoto, 1991) and HGF binding sites with Kd in the range of 250-400 pM observed on a variety of cultured target cell types were sensitive to displacement by soluble heparin (Naldini et al., 1991). Affinity chromatography purification schemes exploited this strong heparin binding to efficiently isolate HGF from low-abundance sources (Nakamura et al., 1987; Gohda et al., 1988; Zarnegar and Michalopoulos, 1989; Rosen et al., 1989; Gherardi et al., 1989; Selden and Hodgson, 1989; Weidner et al., 1990; Rubin et al., 1991). Later studies demonstrated the biological relevance of HS in HGF binding, Met activation and cellular responses (Weidner et al., 1993; Kato et al., 1994; Strain et al., 1994; Zioncheck et al., 1995; Schwall et al., 1996; Hartmann et al., 1998; Sakakura et al., 1999; Day et al., 1999; Sergeant et al., 2000; Seidel et al., 2000; Rubin et al., 2001; Williams and Clark, 2003; Karihaloo et al., 2004). When injected intravenously, HGF has a relatively short half-life (Liu et al., 1997); however, when administered as a complex with heparin, plasma disappearance is much slower, consistent with clearance by hepatic uptake (Kato et al., 1994). Moreover, intravenous injection of soluble heparin into normal humans results in a significant and immediate increase in serum HGF concentration (Seidel et al., 1999). These observations suggest that circulating HGF is rapidly sequestered by HS present on luminal vascular surfaces, which may constitute a widely distributed reservoir of HGF.
HS binding sites are contained primarily in the HGF amino terminal (N) domain (Matsumoto et al., 1991; Okigaki et al., 1992; Mizuno et al., 1994; Sakata et al., 1997; Kinosaki et al., 1998; Hartmann et al., 1998; Zhou et al., 1998; Ultsch et al., 1998; Chirgadze et al., 1999; Zhou et al., 1999; Lyon et al., 1994), but secondary sites are also in the first kringle domain (Lietha et al., 2001). HS and dermatan sulfate (DS) bind to the same sites on NK1, NK2 and full-length HGF, which have identical glycosaminoglycan (GAG) binding properties (Sakata et al., 1997; Lyon et al., 1998; Deakin et al., 2009). HGF binds to syndecan-1, syndecan-2 and syndecan-4; high affinity binding sites are contained within the N-sulfated domains of HS, although the N-sulfates themselves contribute less to binding than nonsulfated alpha-L-iduronic acid residues (Lyon et al., 1994; Ashikari et al., 1995). Affinity is more closely associated with 6-0-sulfation of alpha-D-N-sulfoglucosamine residues than with sulfation at any other position, implying that the structural specificity of HGF-HS interaction is significantly different from that of the fibroblast growth factor family (Lyon et al., 1994; Ashikari et al., 1995). Another feature that distinguishes HGF from other known HS-binding growth factors is the ability to bind DS, which is found on decorin and biglycan (Lyon et al., 1998). DS is an abundant matrix component of the stromal compartment of many organs, implying that retention there must be overcome for HGF delivery to target epithelial and endothelial cells, where HS predominates over DS in basement membranes. This compositional gradient of HGF-binding GAGs is thought to control HGF diffusion from source to target, and act as a reservoir from which relatively high HGF concentrations could be released in a spatially and temporally restricted manner through matrix turnover under various physiological and pathological conditions (Lyon et al., 1998).
Together with GAG binding, HGF signaling is mediated by the cell surface receptor tyrosine kinase Met (Bottaro et al., 1991; Naldini et al., 1991). Although a high-resolution structure of an HGF-Met complex has not yet been obtained, several crystallographic studies of NK1 have refined the basic principles of HGF-Met interaction obtained from functional studies (Ultsch et al., 1998; Chirgadze et al., 1999; Watanabe et al., 2002). In addition to the relatively high affinity Met binding site within NK1, full-length HGF has a lower affinity Met binding site in the light chain that binds to the Met Sema domain; high-resolution structures have been obtained for this interaction (Stamos et al., 2004; Kirchhofer et al., 2004; Kirchhofer et al., 2007; Gherardi et al., 2006). Upon proteolytic conversion of single chain pro-HGF to the mature two-chain heterodimeric form, it undergoes a structural change from a compact, closed conformation to an elongated, open conformation which, through interaction with the Met Sema domain, results in Met kinase activation (Stamos et al., 2004; Kirchhofer et al., 2004; Kirchhofer et al., 2007; Gherardi et al., 2006). Conflicting reports localize the high affinity HGF binding site within the Met ectodomain to the Sema domain (Gherardi et al., 2006), or alternatively, to the more carboxyl terminal Met Ig-like loops 3 and 4 (Basilico et al., 2008). Despite remaining uncertainties, strategies to artificially modulate HGF-driven Met kinase activation have been advanced. Potent competitive antagonists of Met activation have been engineered by altering a secondary HS binding site in K1 (Lietha et al., 2001) and by altering residues in the amino-terminus of the HGF light chain that impair the conformational change accompanying HGF activation (Kirchhofer et al., 2007).
HS and DS interactions with HGF and Met may promote receptor activation and downstream signaling through several mechanisms. HGF binding to cell-surface HS increase local HGF concentrations and promote an intrinsic tendency for HGF to self-associate, which may in turn facilitate and stabilize receptor clustering, kinase activation and potentially the recruitment of intracellular effectors (Schwall et al., 1996; Sakata et al., 1997; Hartmann et al., 1998; Lietha et al., 2001; Kemp et al., 2006; Tolbert et al., 2007). Yet, many details as to how these GAGs promote receptor activation and signaling remain unclear. HS-Met interactions are substantially weaker than HS- or DS-HGF interactions, and their contribution to the stability a ternary HGF-HS-Met complex may not be critical for all HGF responses (Delehedde et al., 2002).
Expression HGF expression has been reported in many tissues throughout the body, including skin, lungs, liver, muscle, pancreas, gastrointestinal tract, salivary glands, thyroid, brain, prostate and seminal vesicles, breast, uterus, placenta, kidney, as well as megakaryocytes and granulocytes (Kinoshita et al., 1989; Noji et al., 1990; Seki et al., 1990; Zarnegar et al., 1990; Nishino et al., 1991; Rubin et al., 1991; Wolf et al., 1991; Defrances et al., 1992; Tsuda et al., 1992; Yanagita et al., 1992; Schirmacher et al., 1993). As a secreted, soluble growth factor that binds strongly to heparan sulfate proteoglycan present in most extracellular matrices and on target cell surfaces, protein staining patterns may indicate target tissue as well as sites of synthesis. This may account for observed immunostaining of epithelia, since there is little evidence of HGF expression by isolated normal epithelial cells. In contrast, normal fibroblasts from many tissues secrete HGF in culture.
Localisation Full-length HGF isoforms are each synthesized as a single polypeptide chain, pre-pro-HGF, containing an amino-terminal signal peptide sequence for insertion into the rough endoplasmic reticulum (RER) and ultimately, secretion. Maturation of pre-pro-HGF is presumed to follow a conventional subcellular pathway for secreted proteins, i.e. from RER to the Golgi apparatus to secretory vesicles that ultimately fuse with the plasma membrane allowing protein release into the extracellular environment. There is evidence for both N-linked (Hara et al., 1993) and O-linked glycosylation (Shimizu et al., 1992) of HGF during maturation, and presumably removal amino-terminal 31 amino acid signal peptide occurs prior to secretion (Miyazawa et al., 1991). The secreted single chain HGF precursor (pro-HGF) is biologically inactive and later converted in the active two-chain disulfide-linked heterodimer by proteolytic cleavage (as described above) in the extracellular space, in plasma, or on target cell surfaces.
Function In most developmental processes and throughout adulthood HGF stimulates cell proliferation, survival, motility, and morphogenesis. These activities were the basis for its discovery as a promoter of liver regeneration (Nakamura et al., 1984; Thaler and Michalopoulos, 1985; Gohda et al., 1986; Nakamura et al., 1989; Miyazawa et al., 1989; Zarnegar and Michalopoulos, 1989) and independently, of cultured epithelial cell growth and motility (Stoker and Perryman, 1985; Stoker et al., 1987; Gherardi et al., 1989; Gherardi and Stoker, 1990; Rubin et al., 1991; Montesano et al., 1991; Weidner et al., 1991; Chan et al., 1991). cDNA cloning of the HGF gene, first reported in 1989, ultimately clarified the identity of hepatocyte growth factor, scatter factor, and a lung fibroblast-derived epithelial cell mitogen concurrently under investigation by researchers around the world.

Embryonic development. HGF and its receptor, Met, are expressed during gastrulation and throughout later phases of vertebrate embryogenesis (Stern et al., 1990; Sonnenberg et al., 1993; Andermarcher et al., 1996). Overlapping expression of both genes persists into the earliest phases of organogenesis in the heart, condensing somites and neural crest cells (Andermarcher et al., 1996), but thereafter HGF is expressed in mesenchymal tissues and Met in the surrounding ectoderm in differentiated somites as well as lungs, liver, placenta, muscle, gut, heart and nervous system (Sonnenberg et al., 1993; Woolf et al., 1995; Andermarcher et al., 1996; Thewke and Seeds, 1996; Birchmeier and Gherardi, 1998; Ishikawa et al., 2001). Studies using tissue explants and cultured cells confirm the suspected role of HGF in epithelial branching morphogenesis, e.g. in the developing lung (Santos et al., 1994; Woolf et al., 1995; Ohmichi et al., 1998).
The expression of HGF and Met genes in ventral motor neurons of the embryonic spinal cord is also consistent with a role in tissue patterning through the regulation of migratory and morphogenic processes, such as axon guidance (Sonnenberg et al., 1993; Ebens et al., 1996; Wong et al., 1997). Functional studies indicate that HGF guides axons of spinal motor neurons to their distant muscle targets in the limbs (Ebens et al., 1996; Wong et al., 1997; Yamamoto et al., 1997) and acts as an essential survival factor for a subpopulation of limb-innervating motoneurons (Wong et al., 1997; Yamamoto et al., 1997). Both HGF and Met are also expressed in the brain and retina during development (E12-13) and in the adult, where signaling supports neuron survival and maturation (Jung et al., 1994; Honda et al., 1995; Yamagata et al., 1995; Hamanoue et al., 1996; Achim et al., 1997; Sun et al., 1999; Thewke and Seeds, 1999).
Loss of HGF or Met function in mice with homozygous gene deletion is embryonic lethal between days E12.5 and E15.5 (Schmidt et al., 1995; Uehara et al., 1995; Bladt et al., 1995). Defects in the proliferation and survival of cells in the liver and placenta result in arrested organogenesis of these and other tissues, underscoring the importance of HGF stimulated mitogenicity and survival in target cells. These models also highlight the importance of HGF as a potent and critical regulator of cell migration. Skeletal muscle progenitor cells that form limb, tongue, and diaphragm musculature normally delaminate from the epithelial dermomyotome of the somites by an epithelial-to-mesenchymal transition and migrate to their final destination where they complete differentiation. Homozygous deletion of Met results in defective delamination and migration of muscle progenitors from the dermomyotome and failure to form the skeletal muscles of the limb and diaphragm (Bladt et al., 1995; Maina et al., 1996; Dietrich et al., 1999; Rosário and Birchmeier, 2003; Christ and Brand-Saberi, 2002). Conversely, HGF overexpression in transgenic mouse embryos induces the inappropriate formation of skeletal muscle in the central nervous system (CNS) through dysregulated migration of Met containing myogenic precursor cells to the neural tube (Takayama et al., 1996).
Mice bearing conditional deletions of HGF or Met also have been used to demonstrate relevance of pathway activation at later developmental stages and in adulthood. Met and epidermal growth factor receptor jointly regulate final nephron number and collecting duct morphology (Ishibe et al., 2009). Mice with a targeted mutation of the gene encoding urokinase plasminogen activator, considered an important HGF activator, have decreased HGF levels and a substantial reduction in neocortical GABAergic interneurons at embryonic and perinatal ages, leading to changes in circuit organization and behavior (Powell et al., 2001; Powell et al., 2003a). Mice with targeted mutation of two critical carboxyl terminal tyrosine residues in Met were found to be phenotypically similar to Met null animals. In contrast, targeting one of those sites and thereby disrupting the consensus for Grb2 binding allowed development to proceed to term, but caused a striking reduction in limb muscle mass and a generalized deficit of secondary fibers, indicating the importance of HGF signaling in late myogenesis (Maina et al., 1996).

Maturity and adult homeostasis. In the developed brain, HGF is expressed in neurons, primarily in the hippocampus, cortex, and the granule cell layer of the cerebellum, as well as in ependymal cells, the chorioid plexus, and the pineal body (Streit et al., 1995). Met is expressed in neurons, preferentially in the CA-1 area of the hippocampus, the cortex, and the septum, as well as in the pons (Jung et al., 1994; Streit et al., 1995; Honda et al., 1995; Yamagata et al., 1995; Thewke and Seeds, 1999). HGF is though to provide a neurotrophic function in the CNS, supporting the survival and reconstruction of specific neurons in response to cerebral injury (Honda et al., 1995). HGF attracts and promotes the growth of cranial motor axons (Caton et al., 2000), induces c-Fos expression and activates the Ras pathway in brain neurons (Streit et al., 1997), stimulates Schwann cell growth (Krasnoselsky et al., 1994) and promotes axon outgrowth of embryonal carcinoma cells (Yang and Park, 1993). HGF stimulates neurite outgrowth in sensory and sympathogenic neurons, as well as enhanced survival and differentiation from progenitors (Maina et al., 1997; Maina et al., 1998).
HGF and Met are expressed in the cerebellum, where development is primarily postnatal and requires extensive cell proliferation and migration. Met is localized in granule cell precursors and cultures of these cells proliferate in response to HGF (Ieraci et al., 2002). HGF also promotes oligodendrocyte progenitor cell proliferation and delays their differentiation into myelinating oligodendrocytes during early postnatal development; subsequent down-regulation of HGF mRNA in the striatum observed between postnatal days 7 to 14 presumably permits differentiation and myelination to proceed (Ohya et al., 2007). Schwann cells, responsible for nerve myelination in the peripheral nervous system, also express Met mRNA (Krasnoselsky et al., 1994). Although Schwann cells are normally quiescent in adulthood, nerve injury and certain diseases such as type 1 neurofibromatosis trigger proliferation through several mitogenic pathways, including that of HGF (Krasnoselsky et al., 1994).
The mammary gland undergoes cyclic morphogenic differentiation during the menstrual cycle, pregnancy and lactation. HGF and Met are expressed and HGF is regulated temporally during mouse mammary development and differentiation (Niranjan et al., 1995; Yang et al., 1995). HGF secreted by fibroblasts acts on mammary myoepithelial and luminal epithelial cells expressing Met, promoting tubulogenesis in underlying myoepithelial cells, branching of the epithelial ductal tree and motogenesis in both cell types (Niranjan et al., 1995; Yang et al., 1995; Yant et al., 1998; Niemann et al., 1998).
HGF production in the adult vascular system is positively regulated by prostaglandins and HGF itself, and negatively regulated by angiotensin II, TGF-beta, glucose and hypoxia (reviewed in Morishita et al., 2002). HGF is induced in cardiac and skeletal muscle in animal models of ischemic injury (Aoki et al., 2000) and serum HGF levels are increased with hypertension, peripheral artery disease and myocardial infarction, consistent with homeostatic and repair functions (reviewed in Morishita et al., 2002).

Wound repair and tissue regeneration. Exogenous administration of the HGF protein or gene promotes angiogenesis without the increased permeability often observed with vascular endothelial cell growth factor (VEGF) treatment (Aoki et al., 2000; Taniyama et al., 2001; Morishita et al., 2004). HGF promotes angiogenesis directly (Sengupta et al., 2003) but also by inducing VEGF expression (Wojta et al., 1999; Gille et al., 1998), and the two factors appear to act synergistically on the vasculature (Van Belle et al., 1998; Xin et al., 2001). These and other findings support the use of HGF for therapeutic angiogenesis to treat peripheral artery disease, myocardial infarction and restenosis after angioplasty. Recent clinical trials indicate that HGF gene therapy is safe and effective for the treatment of critical limb ischemia (Powell et al., 2008; Shigematsu et al., 2010).
HGF signaling supports the natural reconstruction of central and peripheral neuronal networks in response to injury, and/or as a potential therapeutic agent to facilitate wound repair. Both HGF and Met expression are increased in reactive astrocytes in the subacute to chronic stage of spinal cord injury in rats (Shimamura et al., 2007). HGF gene transfer attenuated brain ischemic injury in rats, without cerebral edema, through angiogenic, neuroprotective and neuriotogenic activities, as well as prevention of gliosis (Shimamura et al., 2004; Shimamura et al., 2006). Intrastriatal administration of HGF protein also potently protected hippocampal neurons against postischemic delayed neuronal death (Miyazawa et al., 1996).
Tissue fibrosis is a common pathological consequence of chronic injury to kidneys and lungs. With chronic injury to these organs, the normal production and secretion of growth factors, including HGF, inflammatory cell recruitment, cell proliferation and differentiation, and matrix production and remodeling become increasingly aberrant, leading to matrix overproduction, abnormal organization, fibrotic lesions and scarring. Mice with conditional knockout of Met in the collecting duct of the kidney are more susceptible to interstitial fibrosis and tubular necrosis after unilateral ureteral obstruction, and show a diminished capacity for tubular cell regeneration after release of the obstruction (Ma et al., 2009). Conditional Met knockout targeted to renal podocytes was associated with more severe podocyte apoptosis and albuminurea than in control littermates subjected to nephrotoxic renal damage (Dai et al., 2010). HGF produced in response to injury antagonizes the actions of transforming growth factor-beta (TGF-beta), a critical profibrotic agent, thereby inhibiting fibrosis and preserving normal organ architecture and function (reviewed in Liu, 2004; Mizuno et al., 2008; Crosby and Waters, 2010; Panganiban and Day, 2011). The reciprocal effects of the HGF and TGF-beta signaling pathways occur via direct modulation of intracellular effectors downstream of TGF-beta and HGF receptors in common target cells, as well as by eliciting opposing activities in cells targeted independently (Yo et al., 1998; Gao et al., 2002; Mizuno et al., 2005). TGF-beta induced apoptosis of podocyte, endothelial and tubular epithelial cells, epithelial-to-mesenchymal transition by tubular epithelial cells, and myofibroblastic activation, are critical pathogenic events that are opposed by HGF signaling (reviewed by Böttinger and Bitzer, 2002). An abundance of findings support the therapeutic use of exogenous HGF, the HGF gene, or the induction of endogenous HGF expression, for the treatment of a variety of chronic fibrotic disorders in kidney (Mizuno et al.,1998; Mizuno et al., 2001; Dworkin et al., 2004; Dai et al., 2004; Herrero-Fresneda et al., 2006; reviewed in Liu and Yang, 2006; Mizuno et al., 2008) and lung (Yanagita et al., 1993; Dohi et al., 2000; Mizuno et al., 2005).
HGF signaling is required for liver regeneration (Nakamura et al., 1984; Thaler and Michalopoulos, 1985; Zarnegar and Michalopoulos, 1989; Nakamura et al., 1989; Miyazawa et al., 1989; Okajima et al., 1990). Studies of tissue selective HGF overexpression or Met suppression in genetically engineered animal models confirm and extend earlier studies (Shiota and Kawasaki, 1998; Borowiak et al., 2004; Huh et al., 2004; Paranjpe et al., 2007; Factor et al., 2010). In addition to stimulating the proliferation of mature hepatocytes, HGF contributes to the differentiation and maturation of hepatic progenitor cells (Kamiya et al., 2001). Treatment of animals with exogenous HGF protein or the HGF gene promotes survival in various experimental animal models of acute hepatic failure (Kosai et al., 1998; Nomi et al., 2000) and prevents fibrosis associated with liver cirrhosis (Kaibori et al., 1997; Matsuda et al., 1997). Clinical trials of recombinant human HGF for treatment of patients with fulminant hepatic failure are in progress (Ido and Tsubouchi, 2009).
HGF/Met signaling is required for full-thickness skin wound repair. Damage to the epidermis and dermis of the skin requires reepithelialization of the epidermis and the transient formation of dermal granulation tissue. During reepithelialization, keratinocytes from the wound edge form the hyperproliferative epithelium, which proliferates and migrates over the injured dermis and the granulation tissue. In addition to other important soluble regulators of skin repair such as epidermal and fibroblast growth factor family ligands and transforming growth factor-beta, locally secreted HGF promotes granulation tissue formation and reepithelialization (Yoshida et al., 2003; Chmielowiec et al., 2007). Engineered overexpression or exogenous application of HGF protein, or exogenous HGF gene transfer, to treat full-thickness skin wounds accelerates both processes, as well as vascularization, in rodent models (Toyoda et al., 2001; Yoshida et al., 2003; Bevan et al., 2004; Kunugiza et al., 2006).

Homology Human HGF is highly conserved among mammals but (99.9% amino acid identity between human and chimp, to 91% between human and rat), however, homologs rapidly diverge in birds (75% between human and chicken) and bony fish (50% between human and zebra fish). Structural homology beyond teleosts is partial. More generally, HGF resembles members of the plasminogen family (~38% amino acid identity), in that the mature 2-chain protein contains multiple kringle domains in the amino terminal alpha (or heavy) chain and a serine protease like domain in the carboxyl terminal beta (or light) chain. Unlike the canonical plasminogen family members, HGF is devoid of proteolytic activity (reviewed in Matsumoto and Nakamura, 1996). Of plasminogen family members, HGF is most closely related to macrophage stimulating protein (MSP; 44% amino acid identity; also known as MST1 or HGF-like protein).


Note Polymorphisms in the HGF promoter region affect HGF transcription levels and have been linked to breast cancer (Ma et al., 2009). Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39 (Schultz et al., 2009).

Implicated in

Entity Hepatocellular carcinoma (HCC)
Note HGF signaling has been implicated in a broad spectrum of human cancers. Gains in human chromosome 7q, where both HGF and MET genes are located, occur in approximately 16% of hepatocellular carcinoma (HCC) cases (Breuhahn et al., 2006). HGF signaling drives the transcriptional activation of MET in HCC (Seol et al., 2000), and HGF is overexpressed in the HCC microenvironment relative to normal adult liver levels (Selden et al., 1994; Noguchi et al., 1996). Secretion by stellate cells and myofibroblasts is apparently induced by tumor cell signals; HGF, in turn, stimulates tumor cell invasiveness (D'Errico et al., 1996; Neaud et al., 1997; Guirouilh et al., 2000; Guirouilh et al., 2001). The criticality of HGF in human HCC oncogenesis remains unclear; HGF expression levels did not correlate with patient survival or clinicopathological parameters in at least one study (Ueki et al., 1997), whereas later reports show that higher HGF serum levels negatively correlate with patient survival time (Vejchapipat et al., 2004) and positively correlate with tumor size (Yamagamim et al., 2002). Similarly, there are conflicting reports regarding the role of HGF in HCC animal models. Transgenic HGF expression in mice accelerated chemically induced hepatocarcinogenesis, suggesting an oncogenic effect (Bell et al., 1999; Horiguchi et al., 2002), yet conditional Met knockout also accelerated chemically induced hepatocarcinogenesis, suggesting a suppressor effect (Takami et al., 2007; Marx-Stoetling et al., 2009). Consistent with the latter, HCC cell lines injected into the portal veins of HGF transgenic mice displayed significantly lower rates of experimental liver metastasis than control littermates (Shiota et al., 1996), and recombinant HGF treatment of rats on carcinogenic diets did not increase HCC incidence (Nakanishi et al., 2006).
Entity Head and neck squamous cell carcinoma (HNSCC)
Note Analysis of head and neck squamous cell carcinoma samples revealed significantly increased HGF levels relative to normal mucosa, which correlated a poorly differentiated tumor type and decreased survival rates (Takada et al., 1995). Locally increased HGF production is likely to be due, at least in part, to SCC cell secretion of interleukin-1 (Hasina et al., 1999). Squamous cell carcinoma cells are responsive to esophageal submucosal fibroblast-derived HGF with increased invasiveness (Matsumoto et al., 1994; Iwazawa et al., 1996). The role of HGF in HNSCC was recently reviewed by De Herdt and Baatenburg de Jong, 2008).
Entity Papillary thyroid carcinomas (PTC)
Note Overexpression of both human HGF and MET is found in most papillary thyroid carcinomas, but not other thyroid tumor types. At least one study reported that the majority of these cases appear to possess autocrine HGF/Met signaling (Trovato et al., 1998) although this is controversial (Oyama et al., 1998). Increased MET and HGF expression is associated with a high risk for metastasis and recurrence in children and young adults with PTC (Ramirez et al., 2000). Cell lines established from thyroid carcinomas respond to HGF with increased motility and invasiveness, increased chemokine and VEGF production, and the recruitment of dendritic cells and new blood vessels (de Luca et al., 1999; Scarpino et al., 1999; Scarpino et al., 2000; Scarpino et al., 2003).
Entity Lung cancers
Note HGF has been found in pleural effusion fluid obtained from patients with metastatic lung cancer (Kenworthy et al., 1992); serum HGF levels and tissue levels are also frequently elevated in lung cancer patients (Takigawa et al., 1997; Yamashita et al., 1998). HGF stimulates normal bronchial epithelial cells as well as lung carcinoma cells (Tsao et al., 1993; Olivero et al., 1996; Eagles et al., 1996). Met is well expressed in normal bronchial epithelium and both small cell and non-small cell lung cancers. Somatic MET mutations in these tumor types are relatively frequent (5-13%), occurring primarily in the juxtamembrane and extracellular domains (reviewed in Ma et al., 2008). These do not appear to confer ligand independence, but rather defects in ligand-induced receptor degradation and/or other mechanisms that sustain signaling or increase ligand sensitivity (Ma et al., 2008; Kong-Beltran et al., 2006; Peschard and Park, 2003). Evidence of autocrine HGF signaling in normal bronchiolar epithelium and in non-small cell lung cancer, also has been reported (Tsao et al., 2001). Cigarette smoking induced overexpression of HGF in type II pneumocytes and lung cancer cells (Chen et al., 2006), and HGF inhibited cigarette smoke extract induced apoptosis in human bronchial epithelial cells (Togo et al., 2010). Consistent with these findings, a neutralizing monoclonal antibody directed against HGF significantly reduced tumor burden in mice treated with a tobacco carcinogen (Stabile et al., 2008).
Entity Breast cancer
Note Analysis of breast tumor HGF levels in a large cohort revealed that patients with high values had a significantly shorter relapse-free survival and overall survival when compared to those with low values; in fact, HGF levels were a better independent predictor of relapse-free and overall survival than lymph node involvement (Yamashita et al., 1994; Nagy et al., 1996). Serum HGF levels were also significantly higher than those of healthy controls in about one-third of breast cancer patients, a finding significantly associated with node status, tumor size and histological evidence of venous invasion (Taniguchi et al., 1995; Toi et al., 1998; Sheen-Chen et al., 2005). Removal of the primary tumor decreased the serum HGF levels, suggesting that the elevation was tumor-related (Taniguchi et al., 1995). Almost all patients with recurrent breast cancer also had increased serum HGF level, and patients with liver metastases had higher levels compared to those with other sites of metastases (Taniguchi et al., 1995; Maemura et al., 1998; Eichbaum et al., 2007). Somatic mutations and functional polymorphisms in the HGF gene promoter cause increased HGF production in breast cancer; 51% of African Americans and 15% of individuals of mixed European descent with breast cancer harbor a promoter truncation variant in their breast tumors that which is associated with increased cancer incidence and a substantially younger age of disease onset than those with a wild-type genotype (Ma et al., 2009).
Entity Renal cell carcinoma
Note Inherited missense mutations in the human HGF receptor gene were first found in individuals with hereditary papillary renal carcinoma (HPRC) type 1; similar somatic mutations were also found in a small subset of (PRC) tumor samples (reviewed in Dharmawardana et al., 2004). Trisomy of human chromosome 7, which contains both Met and HGF genes, occurs in 95% of sporadic papillary renal carcinoma and nearly all HPRC cases, where there is always non-random duplication of the mutant allele. Although the role of HGF in the oncogenicity of HPRC and PRC-associated Met mutations is not yet defined, ligand binding clearly promotes cell transformation (Michieli et al., 1999).
Entity Prostate cancer
Note HGF signaling is implicated in prostate cancer (reviewed in Knudsen and Edlund, 2004; Hurle et al., 2005). Met expression was frequently (~50%) found in localized prostate tumor samples and virtually all prostate cancer metastases (Knudsen and Edlund, 2004). The increased frequency of Met expression and loss of androgen responsiveness in advanced disease is consistent with the finding that androgen receptor negatively regulates Met expression (Verras et al., 2007). Plasma HGF level was found to be an independent predictor of metastasis to lymph nodes and disease recurrence following surgery in patients treated for localized prostate cancer (Gupta et al., 2008), and higher plasma HGF levels in hormone refractory patients were associated with a decreased patient survival (Humphrey et al., 2006). Among 174 cytokines analyzed in a collection of prostatic fluid samples, HGF was the most increased in patients with extensive disease compared to those with minimal disease (Fujita et al., 2008).
Entity Brain tumors
Note HGF and Met are expressed in human glioma and medulloblastoma, where increased relative abundance frequently correlate with tumor grade, tumor blood vessel density, and poor prognosis. Overexpression of HGF and/or Met in brain tumor-derived cells enhances their tumorigenicity and growth, while inhibition of HGF or Met in experimental tumor xenografts suppresses tumor growth and angiogenesis (Li et al., 2005; Kim et al., 2006; reviewed in Abounader and Laterra, 2005). A recent pilot study reported that elevated levels of HGF in human cerebrospinal fluid were associated with mortality and recurrence of glioblastoma, suggesting that cerebrospinal fluid HGF level could be of prognostic value for this disease (Garcia-Navarrete et al., 2010). Consistent with the suspected role of HGF in glioma progression, a potent, highly selective, orally bioavailable Met ATP binding antagonist significantly inhibited intracranial brain tumor malignancy and growth in mice (Guessous et al., 2010). Early results from human clinical trials are, unfortunately, not as promising. A recent phase II study of AMG 102 (rilotumumab), a fully human monoclonal antibody against HGF, in patients with recurrent glioblastoma showed that treatment was not associated with significant antitumor activity (Wen et al., 2011).
Entity Digestive tract tumors
Note Overexpression of Met protein and/or amplification of Met was found in 50% of primary human colorectal carcinomas and 70% of liver metastases, suggesting that Met abundance contributes to disease progression (Di Renzo et al., 1995). Met gene amplification also occurs with 10-13% frequency in human gastric cancer (Smolen et al., 2006). Studies of human cultured colorectal tumor cells and tumor tissue samples indicated increased activation of pro-HGF, coincident with increased HGF activator abundance and decreased levels of HGF activator inhibitor-1 (Kataoka et al., 2000a). Several Met kinase inhibitors show potent anti-tumor activity in gastric tumor-derived xenografts (Christensen et al., 2003; Smolen et al., 2006; Zou et al., 2007; Buchanan et al., 2009) and colon derived xenografts (Zhang et al., 2010). A genome-wide expression analysis of colon tumor specimens identified MACC1 as an independent prognostic indicator of metastasis; interestingly, Met is a transcriptional target downstream of MACC1, and expression of the latter promoted HGF-induced colon tumor cell proliferation, invasion as well as tumor growth and metastasis in xenograft models (Stein et al., 2009).
Entity Melanoma
Note Met is normally expressed in melanocytes and the acquisition of HGF expression has been reported in melanoma (Halaban et al., 1993; Natali et al., 1993; Saitoh et al., 1994). HGF transgenic mice display a high frequency of metastatic melanoma in increased sensitivity to UV radiation induced carcinogenesis; indeed, several mouse models of melanoma indicate the prevalence of HGF pathway involvement (reviewed in Walker and Hayward, 2002).
Entity Sarcomas
Note In some sarcomas, Met is overexpressed in malignancy similar to many carcinomas, where HGF is delivered locally in a paracrine manner. However, many sarcomas naturally express HGF and acquire Met expression, resulting in autocrine pathway activation and enhanced oncogenesis, including rhabdomyosarcoma (Chen et al., 2007; Rees et al., 2006; Taulli et al., 2006; Jankowski et al., 2003), leiomyosarcoma (Gao et al., 2009), clear cell sarcoma (Davis et al., 2010) and osteosarcoma (MacEwen et al., 2003; Coltella et al., 2003).
Entity Other diseases
Note Glial cells in the neuroretinas and epiretinal membranes of patients with proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy, respectively, show increased HGF levels, and both glial and pigmented retinal epithelial cells express Met, suggestive of autocrine and/or paracrine roles for HGF in glial cell responses during proliferative vitreoretinal disorders as well as in retinal neovascularization, by stimulating of VEGF release (Hollborn et al., 2004; Cui et al., 2007). Both HGF and its receptor are required for malarial infection (Carrolo et al., 2003).

To be noted

Acknowledgments and support. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.


Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis.
Abounader R, Laterra J.
Neuro Oncol. 2005 Oct;7(4):436-51. (REVIEW)
PMID 16212809
Expression of HGF and cMet in the developing and adult brain.
Achim CL, Katyal S, Wiley CA, Shiratori M, Wang G, Oshika E, Petersen BE, Li JM, Michalopoulos GK.
Brain Res Dev Brain Res. 1997 Sep 20;102(2):299-303.
PMID 9352114
Co-expression of the HGF/SF and c-met genes during early mouse embryogenesis precedes reciprocal expression in adjacent tissues during organogenesis.
Andermarcher E, Surani MA, Gherardi E.
Dev Genet. 1996;18(3):254-66.
PMID 8631159
Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium: up-regulation of essential transcription factor for angiogenesis, ets.
Aoki M, Morishita R, Taniyama Y, Kida I, Moriguchi A, Matsumoto K, Nakamura T, Kaneda Y, Higaki J, Ogihara T.
Gene Ther. 2000 Mar;7(5):417-27.
PMID 10694824
Characterization of heparan sulfate oligosaccharides that bind to hepatocyte growth factor.
Ashikari S, Habuchi H, Kimata K.
J Biol Chem. 1995 Dec 8;270(49):29586-93.
PMID 7494002
A high affinity hepatocyte growth factor-binding site in the immunoglobulin-like region of Met.
Basilico C, Arnesano A, Galluzzo M, Comoglio PM, Michieli P.
J Biol Chem. 2008 Jul 25;283(30):21267-77. Epub 2008 May 21.
PMID 18495663
The five amino acid-deleted isoform of hepatocyte growth factor promotes carcinogenesis in transgenic mice.
Bell A, Chen Q, DeFrances MC, Michalopoulos GK, Zarnegar R.
Oncogene. 1999 Jan 28;18(4):887-95.
PMID 10023664
Diverse and potent activities of HGF/SF in skin wound repair.
Bevan D, Gherardi E, Fan TP, Edwards D, Warn R.
J Pathol. 2004 Jul;203(3):831-8.
PMID 15221943
Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase.
Birchmeier C, Gherardi E.
Trends Cell Biol. 1998 Oct;8(10):404-10. (REVIEW)
PMID 9789329
Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud.
Bladt F, Riethmacher D, Isenmann S, Aguzzi A, Birchmeier C.
Nature. 1995 Aug 31;376(6543):768-71.
PMID 7651534
Met provides essential signals for liver regeneration.
Borowiak M, Garratt AN, Wustefeld T, Strehle M, Trautwein C, Birchmeier C.
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10608-13. Epub 2004 Jul 12.
PMID 15249655
Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product.
Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA.
Science. 1991 Feb 15;251(4995):802-4.
PMID 1846706
TGF-beta signaling in renal disease.
Bottinger EP, Bitzer M.
J Am Soc Nephrol. 2002 Oct;13(10):2600-10. (REVIEW)
PMID 12239251
Dysregulation of growth factor signaling in human hepatocellular carcinoma.
Breuhahn K, Longerich T, Schirmacher P.
Oncogene. 2006 Jun 26;25(27):3787-800. (REVIEW)
PMID 16799620
SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo.
Buchanan SG, Hendle J, Lee PS, Smith CR, Bounaud PY, Jessen KA, Tang CM, Huser NH, Felce JD, Froning KJ, Peterman MC, Aubol BE, Gessert SF, Sauder JM, Schwinn KD, Russell M, Rooney IA, Adams J, Leon BC, Do TH, Blaney JM, Sprengeler PA, Thompson DA, Smyth L, Pelletier LA, Atwell S, Holme K, Wasserman SR, Emtage S, Burley SK, Reich SH.
Mol Cancer Ther. 2009 Dec;8(12):3181-90.
PMID 19934279
Hepatocyte growth factor and its receptor are required for malaria infection.
Carrolo M, Giordano S, Cabrita-Santos L, Corso S, Vigario AM, Silva S, Leiriao P, Carapau D, Armas-Portela R, Comoglio PM, Rodriguez A, Mota MM.
Nat Med. 2003 Nov;9(11):1363-9. Epub 2003 Oct 12.
PMID 14556002
The branchial arches and HGF are growth-promoting and chemoattractant for cranial motor axons.
Caton A, Hacker A, Naeem A, Livet J, Maina F, Bladt F, Klein R, Birchmeier C, Guthrie S.
Development. 2000 Apr;127(8):1751-66.
PMID 10725250
Identification of a competitive HGF antagonist encoded by an alternative transcript.
Chan AM, Rubin JS, Bottaro DP, Hirschfield DW, Chedid M, Aaronson SA.
Science. 1991 Nov 29;254(5036):1382-5.
PMID 1720571
Cigarette smoking induces overexpression of hepatocyte growth factor in type II pneumocytes and lung cancer cells.
Chen JT, Lin TS, Chow KC, Huang HH, Chiou SH, Chiang SF, Chen HC, Chuang TL, Lin TY, Chen CY.
Am J Respir Cell Mol Biol. 2006 Mar;34(3):264-73. Epub 2005 Oct 27.
PMID 16254251
Mutation and expression analyses of the MET and CDKN2A genes in rhabdomyosarcoma with emphasis on MET overexpression.
Chen Y, Takita J, Mizuguchi M, Tanaka K, Ida K, Koh K, Igarashi T, Hanada R, Tanaka Y, Park MJ, Hayashi Y.
Genes Chromosomes Cancer. 2007 Apr;46(4):348-58.
PMID 17243166
Crystal structure of the NK1 fragment of HGF/SF suggests a novel mode for growth factor dimerization and receptor binding.
Chirgadze DY, Hepple JP, Zhou H, Byrd RA, Blundell TL, Gherardi E.
Nat Struct Biol. 1999 Jan;6(1):72-9.
PMID 9886295
c-Met is essential for wound healing in the skin.
Chmielowiec J, Borowiak M, Morkel M, Stradal T, Munz B, Werner S, Wehland J, Birchmeier C, Birchmeier W.
J Cell Biol. 2007 Apr 9;177(1):151-62. Epub 2007 Apr 2.
PMID 17403932
Limb muscle development.
Christ B, Brand-Saberi B.
Int J Dev Biol. 2002;46(7):905-14. (REVIEW)
PMID 12455628
A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo.
Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, Chen J, Wang X, Ruslim L, Blake R, Lipson KE, Ramphal J, Do S, Cui JJ, Cherrington JM, Mendel DB.
Cancer Res. 2003 Nov 1;63(21):7345-55.
PMID 14612533
Hepatocyte growth factor (HGF)/NK1 is a naturally occurring HGF/scatter factor variant with partial agonist/antagonist activity.
Cioce V, Csaky KG, Chan AM, Bottaro DP, Taylor WG, Jensen R, Aaronson SA, Rubin JS.
J Biol Chem. 1996 May 31;271(22):13110-5.
PMID 8662798
Role of the MET/HGF receptor in proliferation and invasive behavior of osteosarcoma.
Coltella N, Manara MC, Cerisano V, Trusolino L, Di Renzo MF, Scotlandi K, Ferracini R.
FASEB J. 2003 Jun;17(9):1162-4. Epub 2003 Apr 22.
PMID 12709413
Epithelial repair mechanisms in the lung.
Crosby LM, Waters CM.
Am J Physiol Lung Cell Mol Physiol. 2010 Jun;298(6):L715-31. Epub 2010 Apr 2. (REVIEW)
PMID 20363851
Stage specificity of novel growth factor expression during development of proliferative vitreoretinopathy.
Cui JZ, Chiu A, Maberley D, Ma P, Samad A, Matsubara JA.
Eye (Lond). 2007 Feb;21(2):200-8. Epub 2006 Mar 10.
PMID 16531976
Liver hepatocyte growth factor does not always correlate with hepatocellular proliferation in human liver lesions: its specific receptor c-met does.
D'Errico A, Fiorentino M, Ponzetto A, Daikuhara Y, Tsubouchi H, Brechot C, Scoazec JY, Grigioni WF.
Hepatology. 1996 Jul;24(1):60-4.
PMID 8707284
Hepatocyte growth factor signaling ameliorates podocyte injury and proteinuria.
Dai C, Saleem MA, Holzman LB, Mathieson P, Liu Y.
Kidney Int. 2010 Jun;77(11):962-73. Epub 2010 Mar 10.
PMID 20375988
Intravenous administration of hepatocyte growth factor gene ameliorates diabetic nephropathy in mice.
Dai C, Yang J, Bastacky S, Xia J, Li Y, Liu Y.
J Am Soc Nephrol. 2004 Oct;15(10):2637-47.
PMID 15466268
Identification of the receptor tyrosine kinase c-Met and its ligand, hepatocyte growth factor, as therapeutic targets in clear cell sarcoma.
Davis IJ, McFadden AW, Zhang Y, Coxon A, Burgess TL, Wagner AJ, Fisher DE.
Cancer Res. 2010 Jan 15;70(2):639-45. Epub 2010 Jan 12.
PMID 20068147
Differential signaling by alternative HGF isoforms through c-Met: activation of both MAP kinase and PI 3-kinase pathways is insufficient for mitogenesis.
Day RM, Cioce V, Breckenridge D, Castagnino P, Bottaro DP.
Oncogene. 1999 Jun 3;18(22):3399-406.
PMID 10362361
HGF and c-MET as potential orchestrators of invasive growth in head and neck squamous cell carcinoma.
De Herdt MJ, Baatenburg de Jong RJ.
Front Biosci. 2008 Jan 1;13:2516-26. (REVIEW)
PMID 17981731
The binding properties of minimal oligosaccharides reveal a common heparan sulfate/dermatan sulfate-binding site in hepatocyte growth factor/scatter factor that can accommodate a wide variety of sulfation patterns.
Deakin JA, Blaum BS, Gallagher JT, Uhrin D, Lyon M.
J Biol Chem. 2009 Mar 6;284(10):6311-21. Epub 2008 Dec 29.
PMID 19114710
The presence of hepatocyte growth factor in the developing rat.
Defrances MC, Wolf HK, Michalopoulos GK, Zarnegar R.
Development. 1992 Oct;116(2):387-95.
PMID 1286614
Characterization of placental bikunin, a novel human serine protease inhibitor.
Delaria KA, Muller DK, Marlor CW, Brown JE, Das RC, Roczniak SO, Tamburini PP.
J Biol Chem. 1997 May 2;272(18):12209-14.
PMID 9115295
Hepatocyte growth factor/scatter factor binds to small heparin-derived oligosaccharides and stimulates the proliferation of human HaCaT keratinocytes.
Delehedde M, Lyon M, Vidyasagar R, McDonnell TJ, Fernig DG.
J Biol Chem. 2002 Apr 5;277(14):12456-62. Epub 2002 Jan 17.
PMID 11799124
Functional characterization of Kunitz domains in hepatocyte growth factor activator inhibitor type 1.
Denda K, Shimomura T, Kawaguchi T, Miyazawa K, Kitamura N.
J Biol Chem. 2002 Apr 19;277(16):14053-9. Epub 2002 Jan 22.
PMID 11805118
Hereditary papillary renal carcinoma type I.
Dharmawardana PG, Giubellino A, Bottaro DP.
Curr Mol Med. 2004 Dec;4(8):855-68. (REVIEW)
PMID 15579033
Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer.
Di Renzo MF, Olivero M, Giacomini A, Porte H, Chastre E, Mirossay L, Nordlinger B, Bretti S, Bottardi S, Giordano S, et al.
Clin Cancer Res. 1995 Feb;1(2):147-54.
PMID 9815967
The role of SF/HGF and c-Met in the development of skeletal muscle.
Dietrich S, Abou-Rebyeh F, Brohmann H, Bladt F, Sonnenberg-Riethmacher E, Yamaai T, Lumsden A, Brand-Saberi B, Birchmeier C.
Development. 1999 Apr;126(8):1621-9.
PMID 10079225
Hepatocyte growth factor attenuates collagen accumulation in a murine model of pulmonary fibrosis.
Dohi M, Hasegawa T, Yamamoto K, Marshall BC.
Am J Respir Crit Care Med. 2000 Dec;162(6):2302-7.
PMID 11112155
Hepatocyte growth factor ameliorates progression of interstitial fibrosis in rats with established renal injury.
Dworkin LD, Gong R, Tolbert E, Centracchio J, Yano N, Zanabli AR, Esparza A, Rifai A.
Kidney Int. 2004 Feb;65(2):409-19.
PMID 14717911
Hepatocyte growth factor/scatter factor is present in most pleural effusion fluids from cancer patients.
Eagles G, Warn A, Ball RY, Baillie-Johnson H, Arakaki N, Daikuhara Y, Warn RM.
Br J Cancer. 1996 Feb;73(3):377-81.
PMID 8562345
Hepatocyte growth factor/scatter factor is an axonal chemoattractant and a neurotrophic factor for spinal motor neurons.
Ebens A, Brose K, Leonardo ED, Hanson MG Jr, Bladt F, Birchmeier C, Barres BA, Tessier-Lavigne M.
Neuron. 1996 Dec;17(6):1157-72.
PMID 8982163
Serum levels of hepatocyte growth factor/scatter factor in patients with liver metastases from breast cancer.
Eichbaum MH, de Rossi TM, Kaul S, Bruckner T, Schneeweiss A, Sohn C.
Tumour Biol. 2007;28(1):36-44. Epub 2006 Dec 1.
PMID 17143015
Hepatocyte growth factor activator (HGFA): molecular structure and interactions with HGFA inhibitor-1 (HAI-1).
Eigenbrot C, Ganesan R, Kirchhofer D.
FEBS J. 2010 May;277(10):2215-22. Epub 2010 Apr 9. (REVIEW)
PMID 20402765
Loss of c-Met disrupts gene expression program required for G2/M progression during liver regeneration in mice.
Factor VM, Seo D, Ishikawa T, Kaposi-Novak P, Marquardt JU, Andersen JB, Conner EA, Thorgeirsson SS.
PLoS One. 2010 Sep 16;5(9). pii: e12739.
PMID 20862286
Cytokine profiling of prostatic fluid from cancerous prostate glands identifies cytokines associated with extent of tumor and inflammation.
Fujita K, Ewing CM, Sokoll LJ, Elliott DJ, Cunningham M, De Marzo AM, Isaacs WB, Pavlovich CP.
Prostate. 2008 Jun 1;68(8):872-82.
PMID 18361406
Processing of hepatocyte growth factor to the heterodimeric form is required for biological activity.
Gak E, Taylor WG, Chan AM, Rubin JS.
FEBS Lett. 1992 Oct 12;311(1):17-21.
PMID 1383032
Therapeutic potential of hepatocyte growth factor/scatter factor neutralizing antibodies: inhibition of tumor growth in both autocrine and paracrine hepatocyte growth factor/scatter factor:c-Met-driven models of leiomyosarcoma.
Gao CF, Xie Q, Zhang YW, Su Y, Zhao P, Cao B, Furge K, Sun J, Rex K, Osgood T, Coxon A, Burgess TL, Vande Woude GF.
Mol Cancer Ther. 2009 Oct;8(10):2803-10.
PMID 19825800
Hepatocyte growth factor gene therapy retards the progression of chronic obstructive nephropathy.
Gao X, Mae H, Ayabe N, Takai T, Oshima K, Hattori M, Ueki T, Fujimoto J, Tanizawa T.
Kidney Int. 2002 Oct;62(4):1238-48.
PMID 12234294
Hepatocyte growth factor in cerebrospinal fluid is associated with mortality and recurrence of glioblastoma, and could be of prognostic value.
Garcia-Navarrete R, Garcia E, Arrieta O, Sotelo J.
J Neurooncol. 2010 May;97(3):347-51. Epub 2009 Oct 25.
PMID 19856144
Structural basis of hepatocyte growth factor/scatter factor and MET signalling.
Gherardi E, Sandin S, Petoukhov MV, Finch J, Youles ME, Ofverstedt LG, Miguel RN, Blundell TL, Vande Woude GF, Skoglund U, Svergun DI.
Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4046-51. Epub 2006 Mar 6.
PMID 16537482
Hepatocyte growth factor/scatter factor (HGF/SF) induces vascular permeability factor (VPF/VEGF) expression by cultured keratinocytes.
Gille J, Khalik M, Konig V, Kaufmann R.
J Invest Dermatol. 1998 Dec;111(6):1160-5.
PMID 9856833
Purification and partial characterization of hepatocyte growth factor from plasma of a patient with fulminant hepatic failure.
Gohda E, Tsubouchi H, Nakayama H, Hirono S, Sakiyama O, Takahashi K, Miyazaki H, Hashimoto S, Daikuhara Y.
J Clin Invest. 1988 Feb;81(2):414-9.
PMID 3276728
An orally bioavailable c-Met kinase inhibitor potently inhibits brain tumor malignancy and growth.
Guessous F, Zhang Y, diPierro C, Marcinkiewicz L, Sarkaria J, Schiff D, Buchanan S, Abounader R.
Anticancer Agents Med Chem. 2010 Jan;10(1):28-35.
PMID 20015006
Expression of hepatocyte growth factor in human hepatocellular carcinoma.
Guirouilh J, Le Bail B, Boussarie L, Balabaud C, Bioulac-Sage P, Desmouliere A, Schuppan D, Rosenbaum J.
J Hepatol. 2001 Jan;34(1):78-83.
PMID 11211911
Predictive value of plasma hepatocyte growth factor/scatter factor levels in patients with clinically localized prostate cancer.
Gupta A, Karakiewicz PI, Roehrborn CG, Lotan Y, Zlotta AR, Shariat SF.
Clin Cancer Res. 2008 Nov 15;14(22):7385-90.
PMID 19010854
met and HGF-SF in normal melanocytes and melanoma cells.
Halaban R, Rubin JS, White W.
EXS. 1993;65:329-39. (REVIEW)
PMID 8380740
Neurotrophic effect of hepatocyte growth factor on central nervous system neurons in vitro.
Hamanoue M, Takemoto N, Matsumoto K, Nakamura T, Nakajima K, Kohsaka S.
J Neurosci Res. 1996 Mar 1;43(5):554-64.
PMID 8833090
Structural study of the N-linked oligosaccharides of hepatocyte growth factor by two-dimensional sugar mapping.
Hara H, Nakae Y, Sogabe T, Ihara I, Ueno S, Sakai H, Inoue H, Shimizu S, Nakamura T, Shimizu N.
J Biochem. 1993 Jul;114(1):76-82.
PMID 8407880
Engineered mutants of HGF/SF with reduced binding to heparan sulphate proteoglycans, decreased clearance and enhanced activity in vivo.
Hartmann G, Prospero T, Brinkmann V, Ozcelik C, Winter G, Hepple J, Batley S, Bladt F, Sachs M, Birchmeier C, Birchmeier W, Gherardi E.
Curr Biol. 1998 Jan 29;8(3):125-34.
PMID 9443912
Autocrine and paracrine motility factors and their involvement in invasiveness in a human oral carcinoma cell line.
Hasina R, Matsumoto K, Matsumoto-Taniura N, Kato I, Sakuda M, Nakamura T.
Br J Cancer. 1999 Aug;80(11):1708-17.
PMID 10468286
HGF gene therapy attenuates renal allograft scarring by preventing the profibrotic inflammatory-induced mechanisms.
Herrero-Fresneda I, Torras J, Franquesa M, Vidal A, Cruzado JM, Lloberas N, Fillat C, Grinyo JM.
Kidney Int. 2006 Jul;70(2):265-74. Epub 2006 May 17.
PMID 16710352
Hepatocyte growth factor is a preferred in vitro substrate for human hepsin, a membrane-anchored serine protease implicated in prostate and ovarian cancers.
Herter S, Piper DE, Aaron W, Gabriele T, Cutler G, Cao P, Bhatt AS, Choe Y, Craik CS, Walker N, Meininger D, Hoey T, Austin RJ.
Biochem J. 2005 Aug 15;390(Pt 1):125-36.
PMID 15839837
Glial cell expression of hepatocyte growth factor in vitreoretinal proliferative disease.
Hollborn M, Krausse C, Iandiev I, Yafai Y, Tenckhoff S, Bigl M, Schnurrbusch UE, Limb GA, Reichenbach A, Kohen L, Wolf S, Wiedemann P, Bringmann A.
Lab Invest. 2004 Aug;84(8):963-72.
PMID 15156160
Localization and functional coupling of HGF and c-Met/HGF receptor in rat brain: implication as neurotrophic factor.
Honda S, Kagoshima M, Wanaka A, Tohyama M, Matsumoto K, Nakamura T.
Brain Res Mol Brain Res. 1995 Sep;32(2):197-210.
PMID 7500831
Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine.
Horiguchi N, Takayama H, Toyoda M, Otsuka T, Fukusato T, Merlino G, Takagi H, Mori M.
Oncogene. 2002 Mar 14;21(12):1791-9.
PMID 11896611
Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair.
Huh CG, Factor VM, Sanchez A, Uchida K, Conner EA, Thorgeirsson SS.
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4477-82.
PMID 15070743
Prognostic significance of plasma scatter factor/hepatocyte growth factor levels in patients with metastatic hormone- refractory prostate cancer: results from cancer and leukemia group B 150005/9480.
Humphrey PA, Halabi S, Picus J, Sanford B, Vogelzang NJ, Small EJ, Kantoff PW.
Clin Genitourin Cancer. 2006 Mar;4(4):269-74.
PMID 16729910
Hepatocyte growth factor/scatter factor and prostate cancer: a review.
Hurle RA, Davies G, Parr C, Mason MD, Jenkins SA, Kynaston HG, Jiang WG.
Histol Histopathol. 2005 Oct;20(4):1339-49. (REVIEW)
PMID 16136515
Translational research to identify clinical applications of hepatocyte growth factor.
Ido A, Tsubouchi H.
Hepatol Res. 2009 Aug;39(8):739-47. Epub 2009 Jul 13.
PMID 19624764
Viable hypomorphic signaling mutant of the Met receptor reveals a role for hepatocyte growth factor in postnatal cerebellar development.
Ieraci A, Forni PE, Ponzetto C.
Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):15200-5. Epub 2002 Oct 23.
PMID 12397180
Met and the epidermal growth factor receptor act cooperatively to regulate final nephron number and maintain collecting duct morphology.
Ishibe S, Karihaloo A, Ma H, Zhang J, Marlier A, Mitobe M, Togawa A, Schmitt R, Czyczk J, Kashgarian M, Geller DS, Thorgeirsson SS, Cantley LG.
Development. 2009 Jan;136(2):337-45.
PMID 19103805
Immunolocalization of hepatocyte growth factor and its receptor (c-Met) during mouse liver development.
Ishikawa KS, Masui T, Ishikawa K, Shiojiri N.
Histochem Cell Biol. 2001 Nov;116(5):453-62. Epub 2001 Nov 9.
PMID 11735009
Primary human fibroblasts induce diverse tumor invasiveness: involvement of HGF as an important paracrine factor.
Iwazawa T, Shiozaki H, Doki Y, Inoue M, Tamura S, Matsui S, Monden T, Matsumoto K, Nakamura T, Monden M.
Jpn J Cancer Res. 1996 Nov;87(11):1134-42.
PMID 9045942
Both hepatocyte growth factor (HGF) and stromal-derived factor-1 regulate the metastatic behavior of human rhabdomyosarcoma cells, but only HGF enhances their resistance to radiochemotherapy.
Jankowski K, Kucia M, Wysoczynski M, Reca R, Zhao D, Trzyna E, Trent J, Peiper S, Zembala M, Ratajczak J, Houghton P, Janowska-Wieczorek A, Ratajczak MZ.
Cancer Res. 2003 Nov 15;63(22):7926-35.
PMID 14633723
Expression and functional interaction of hepatocyte growth factor-scatter factor and its receptor c-met in mammalian brain.
Jung W, Castren E, Odenthal M, Vande Woude GF, Ishii T, Dienes HP, Lindholm D, Schirmacher P.
J Cell Biol. 1994 Jul;126(2):485-94.
PMID 8034747
Stimulation of liver regeneration and function after partial hepatectomy in cirrhotic rats by continuous infusion of recombinant human hepatocyte growth factor.
Kaibori M, Kwon AH, Nakagawa M, Wei T, Uetsuji S, Kamiyama Y, Okumura T, Kitamura N.
J Hepatol. 1997 Aug;27(2):381-90.
PMID 9288614
Oncostatin M and hepatocyte growth factor induce hepatic maturation via distinct signaling pathways.
Kamiya A, Kinoshita T, Miyajima A.
FEBS Lett. 2001 Mar 9;492(1-2):90-4.
PMID 11248243
Hepatocyte growth factor-mediated renal epithelial branching morphogenesis is regulated by glypican-4 expression.
Karihaloo A, Kale S, Rosenblum ND, Cantley LG.
Mol Cell Biol. 2004 Oct;24(19):8745-52.
PMID 15367691
Activation of hepatocyte growth factor/scatter factor in colorectal carcinoma.
Kataoka H, Hamasuna R, Itoh H, Kitamura N, Koono M.
Cancer Res. 2000a Nov 1;60(21):6148-59.
PMID 11085539
Hepatocyte growth factor activator inhibitor type 1 is a specific cell surface binding protein of hepatocyte growth factor activator (HGFA) and regulates HGFA activity in the pericellular microenvironment.
Kataoka H, Shimomura T, Kawaguchi T, Hamasuna R, Itoh H, Kitamura N, Miyazawa K, Koono M.
J Biol Chem. 2000b Dec 22;275(51):40453-62.
PMID 11013244
Hepatocyte growth factor immobilized onto culture substrates through heparin and matrigel enhances DNA synthesis in primary rat hepatocytes.
Kato S, Ishii T, Hara H, Sugiura N, Kimata K, Akamatsu N.
Exp Cell Res. 1994 Mar;211(1):53-8.
PMID 8125158
Purification and cloning of hepatocyte growth factor activator inhibitor type 2, a Kunitz-type serine protease inhibitor.
Kawaguchi T, Qin L, Shimomura T, Kondo J, Matsumoto K, Denda K, Kitamura N.
J Biol Chem. 1997 Oct 31;272(44):27558-64.
PMID 9346890
Signalling by HGF/SF and Met: the role of heparan sulphate co-receptors.
Kemp LE, Mulloy B, Gherardi E.
Biochem Soc Trans. 2006 Jun;34(Pt 3):414-7. (REVIEW)
PMID 16709175
The presence of scatter factor in patients with metastatic spread to the pleura.
Kenworthy P, Dowrick P, Baillie-Johnson H, McCann B, Tsubouchi H, Arakaki N, Daikuhara Y, Warn RM.
Br J Cancer. 1992 Aug;66(2):243-7.
PMID 1387000
Systemic anti-hepatocyte growth factor monoclonal antibody therapy induces the regression of intracranial glioma xenografts.
Kim KJ, Wang L, Su YC, Gillespie GY, Salhotra A, Lal B, Laterra J.
Clin Cancer Res. 2006 Feb 15;12(4):1292-8.
PMID 16489086
Analysis of deleted variant of hepatocyte growth factor by alanine scanning mutagenesis: identification of residues essential for its biological function and generation of mutants with enhanced mitogenic activity on rat hepatocytes.
Kinosaki M, Yamaguchi K, Murakami A, Morinaga T, Ueda M, Higashio K.
FEBS Lett. 1998 Aug 28;434(1-2):165-70.
PMID 9738471
Marked increase of HGF mRNA in non-parenchymal liver cells of rats treated with hepatotoxins.
Kinoshita T, Tashiro K, Nakamura T.
Biochem Biophys Res Commun. 1989 Dec 29;165(3):1229-34.
PMID 2692563
Utilizing the activation mechanism of serine proteases to engineer hepatocyte growth factor into a Met antagonist.
Kirchhofer D, Lipari MT, Santell L, Billeci KL, Maun HR, Sandoval WN, Moran P, Ridgway J, Eigenbrot C, Lazarus RA.
Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5306-11. Epub 2007 Mar 19.
PMID 17372204
Prostate cancer and the met hepatocyte growth factor receptor.
Knudsen BS, Edlund M.
Adv Cancer Res. 2004;91:31-67. (REVIEW)
PMID 15327888
Somatic mutations lead to an oncogenic deletion of met in lung cancer.
Kong-Beltran M, Seshagiri S, Zha J, Zhu W, Bhawe K, Mendoza N, Holcomb T, Pujara K, Stinson J, Fu L, Severin C, Rangell L, Schwall R, Amler L, Wickramasinghe D, Yauch R.
Cancer Res. 2006 Jan 1;66(1):283-9.
PMID 16397241
Abrogation of Fas-induced fulminant hepatic failure in mice by hepatocyte growth factor.
Kosai K, Matsumoto K, Nagata S, Tsujimoto Y, Nakamura T.
Biochem Biophys Res Commun. 1998 Mar 27;244(3):683-90.
PMID 9535725
Hepatocyte growth factor is a mitogen for Schwann cells and is present in neurofibromas.
Krasnoselsky A, Massay MJ, DeFrances MC, Michalopoulos G, Zarnegar R, Ratner N.
J Neurosci. 1994 Dec;14(12):7284-90.
PMID 7996175
Acceleration of wound healing by combined gene transfer of hepatocyte growth factor and prostacyclin synthase with Shima Jet.
Kunugiza Y, Tomita N, Taniyama Y, Tomita T, Osako MK, Tamai K, Tanabe T, Kaneda Y, Yoshikawa H, Morishita R.
Gene Ther. 2006 Aug;13(15):1143-52. Epub 2006 Mar 30.
PMID 16572191
Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase, an epithelial membrane serine protease.
Lee SL, Dickson RB, Lin CY.
J Biol Chem. 2000 Nov 24;275(47):36720-5.
PMID 10962009
The scatter factor/hepatocyte growth factor: c-met pathway in human embryonal central nervous system tumor malignancy.
Li Y, Lal B, Kwon S, Fan X, Saldanha U, Reznik TE, Kuchner EB, Eberhart C, Laterra J, Abounader R.
Cancer Res. 2005 Oct 15;65(20):9355-62.
PMID 16230398
Crystal structures of NK1-heparin complexes reveal the basis for NK1 activity and enable engineering of potent agonists of the MET receptor.
Lietha D, Chirgadze DY, Mulloy B, Blundell TL, Gherardi E.
EMBO J. 2001 Oct 15;20(20):5543-55.
PMID 11597998
Existence of two nonlinear elimination mechanisms for hepatocyte growth factor in rats.
Liu KX, Kato Y, Kato M, Kaku TI, Nakamura T, Sugiyama Y.
Am J Physiol. 1997 Nov;273(5 Pt 1):E891-7.
PMID 9374673
Hepatocyte growth factor: new arsenal in the fights against renal fibrosis?
Liu Y, Yang J.
Kidney Int. 2006 Jul;70(2):238-40. (REVIEW)
PMID 16838037
Hepatocyte growth factor in kidney fibrosis: therapeutic potential and mechanisms of action.
Liu Y.
Am J Physiol Renal Physiol. 2004 Jul;287(1):F7-16. (REVIEW)
PMID 15180923
Generation and characterization of a competitive antagonist of human hepatocyte growth factor, HGF/NK1.
Lokker NA, Godowski PJ.
J Biol Chem. 1993 Aug 15;268(23):17145-50.
PMID 8349603
Structure-function analysis of hepatocyte growth factor: identification of variants that lack mitogenic activity yet retain high affinity receptor binding.
Lokker NA, Mark MR, Luis EA, Bennett GL, Robbins KA, Baker JB, Godowski PJ.
EMBO J. 1992 Jul;11(7):2503-10.
PMID 1321034
Hepatocyte growth factor/scatter factor binds with high affinity to dermatan sulfate.
Lyon M, Deakin JA, Rahmoune H, Fernig DG, Nakamura T, Gallagher JT.
J Biol Chem. 1998 Jan 2;273(1):271-8.
PMID 9417075
Somatic mutation and functional polymorphism of a novel regulatory element in the HGF gene promoter causes its aberrant expression in human breast cancer.
Ma J, DeFrances MC, Zou C, Johnson C, Ferrell R, Zarnegar R.
J Clin Invest. 2009 Mar;119(3):478-91. doi: 10.1172/JCI36640. Epub 2009 Feb 2.
PMID 19188684
Expression and mutational analysis of MET in human solid cancers.
Ma PC, Tretiakova MS, MacKinnon AC, Ramnath N, Johnson C, Dietrich S, Seiwert T, Christensen JG, Jagadeeswaran R, Krausz T, Vokes EE, Husain AN, Salgia R.
Genes Chromosomes Cancer. 2008 Dec;47(12):1025-37.
PMID 18709663
c-Met tyrosine kinase receptor expression and function in human and canine osteosarcoma cells.
MacEwen EG, Kutzke J, Carew J, Pastor J, Schmidt JA, Tsan R, Thamm DH, Radinsky R.
Clin Exp Metastasis. 2003;20(5):421-30.
PMID 14524531
Serum concentration of hepatocyte growth factor in patients with metastatic breast cancer.
Maemura M, Iino Y, Yokoe T, Horiguchi J, Takei H, Koibuchi Y, Horii Y, Takeyoshi I, Ohwada S, Morishita Y.
Cancer Lett. 1998 Apr 24;126(2):215-20.
PMID 9585069
Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development.
Maina F, Casagranda F, Audero E, Simeone A, Comoglio PM, Klein R, Ponzetto C.
Cell. 1996 Nov 1;87(3):531-42.
PMID 8898205
Multiple roles for hepatocyte growth factor in sympathetic neuron development.
Maina F, Hilton MC, Andres R, Wyatt S, Klein R, Davies AM.
Neuron. 1998 May;20(5):835-46.
PMID 9620689
Presence of urokinase in serum-free primary rat hepatocyte cultures and its role in activating hepatocyte growth factor.
Mars WM, Kim TH, Stolz DB, Liu ML, Michalopoulos GK.
Cancer Res. 1996 Jun 15;56(12):2837-43.
PMID 8665523
Immediate early detection of urokinase receptor after partial hepatectomy and its implications for initiation of liver regeneration.
Mars WM, Liu ML, Kitson RP, Goldfarb RH, Gabauer MK, Michalopoulos GK.
Hepatology. 1995 Jun;21(6):1695-701.
PMID 7768515
Activation of hepatocyte growth factor by the plasminogen activators uPA and tPA.
Mars WM, Zarnegar R, Michalopoulos GK.
Am J Pathol. 1993 Sep;143(3):949-58.
PMID 8362987
Hepatocarcinogenesis in mice with a conditional knockout of the hepatocyte growth factor receptor c-Met.
Marx-Stoelting P, Borowiak M, Knorpp T, Birchmeier C, Buchmann A, Schwarz M.
Int J Cancer. 2009 Apr 15;124(8):1767-72.
PMID 19123478
Sequestration of a hepatocyte growth factor in extracellular matrix in normal adult rat liver.
Masumoto A, Yamamoto N.
Biochem Biophys Res Commun. 1991 Jan 15;174(1):90-5.
PMID 1824922
Preventive and therapeutic effects in rats of hepatocyte growth factor infusion on liver fibrosis/cirrhosis.
Matsuda Y, Matsumoto K, Yamada A, Ichida T, Asakura H, Komoriya Y, Nishiyama E, Nakamura T.
Hepatology. 1997 Jul;26(1):81-9.
PMID 9214455
Emerging multipotent aspects of hepatocyte growth factor.
Matsumoto K, Nakamura T.
J Biochem. 1996 Apr;119(4):591-600. (REVIEW)
PMID 8743556
Mutant Met-mediated transformation is ligand-dependent and can be inhibited by HGF antagonists.
Michieli P, Basilico C, Pennacchietti S, Maffe A, Tamagnone L, Giordano S, Bardelli A, Comoglio PM.
Oncogene. 1999 Sep 16;18(37):5221-31.
PMID 10498872
Activation of hepatocyte growth factor in the injured tissues is mediated by hepatocyte growth factor activator.
Miyazawa K, Shimomura T, Kitamura N.
J Biol Chem. 1996 Feb 16;271(7):3615-8.
PMID 8631970
Hairpin loop and second kringle domain are essential sites for heparin binding and biological activity of hepatocyte growth factor.
Mizuno K, Inoue H, Hagiya M, Shimizu S, Nose T, Shimohigashi Y, Nakamura T.
J Biol Chem. 1994 Jan 14;269(2):1131-6.
PMID 8288571
Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronic renal disease.
Mizuno S, Kurosawa T, Matsumoto K, Mizuno-Horikawa Y, Okamoto M, Nakamura T.
J Clin Invest. 1998 May 1;101(9):1827-34.
PMID 9576745
HGF as a renotrophic and anti-fibrotic regulator in chronic renal disease.
Mizuno S, Matsumoto K, Nakamura T.
Front Biosci. 2008 May 1;13:7072-86. (REVIEW)
PMID 18508717
Differential effects of hepatocyte growth factor isoforms on epithelial and endothelial tubulogenesis.
Montesano R, Soriano JV, Malinda KM, Ponce ML, Bafico A, Kleinman HK, Bottaro DP, Aaronson SA.
Cell Growth Differ. 1998 May;9(5):355-65.
PMID 9607557
Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease.
Morishita R, Aoki M, Hashiya N, Makino H, Yamasaki K, Azuma J, Sawa Y, Matsuda H, Kaneda Y, Ogihara T.
Hypertension. 2004 Aug;44(2):203-9. Epub 2004 Jul 6.
PMID 15238569
Hepatocyte growth factor/scatter factor expression and c-met in primary breast cancer.
Nagy J, Curry GW, Hillan KJ, McKay IC, Mallon E, Purushotham AD, George WD.
Surg Oncol. 1996 Feb;5(1):15-21.
PMID 8837300
Activation of hepatocyte growth factor by proteolytic conversion of a single chain form to a heterodimer.
Naka D, Ishii T, Yoshiyama Y, Miyazawa K, Hara H, Hishida T, Kidamura N.
J Biol Chem. 1992 Oct 5;267(28):20114-9.
PMID 1328193
Molecular cloning and expression of human hepatocyte growth factor.
Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, Tashiro K, Shimizu S.
Nature. 1989 Nov 23;342(6248):440-3.
PMID 2531289
Effect of hepatocyte growth factor on endogenous hepatocarcinogenesis in rats fed a choline-deficient L-amino acid-defined diet.
Nakanishi C, Moriuchi A, Ido A, Numata M, Kim ID, Kusumoto K, Hasuike S, Abe H, Nagata K, Akiyama Y, Uto H, Kataoka H, Tsubouchi H.
Oncol Rep. 2006 Jul;16(1):25-31.
PMID 16786119
Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor.
Naldini L, Tamagnone L, Vigna E, Sachs M, Hartmann G, Birchmeier W, Daikuhara Y, Tsubouchi H, Blasi F, Comoglio PM.
EMBO J. 1992 Dec;11(13):4825-33.
PMID 1334458
Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor.
Naldini L, Weidner KM, Vigna E, Gaudino G, Bardelli A, Ponzetto C, Narsimhan RP, Hartmann G, Zarnegar R, Michalopoulos GK, et al.
EMBO J. 1991 Oct;10(10):2867-78.
PMID 1655405
Expression of the c-Met/HGF receptor in human melanocytic neoplasms: demonstration of the relationship to malignant melanoma tumour progression.
Natali PG, Nicotra MR, Di Renzo MF, Prat M, Bigotti A, Cavaliere R, Comoglio PM.
Br J Cancer. 1993 Oct;68(4):746-50.
PMID 8104462
Human hepatic myofibroblasts increase invasiveness of hepatocellular carcinoma cells: evidence for a role of hepatocyte growth factor.
Neaud V, Faouzi S, Guirouilh J, Le Bail B, Balabaud C, Bioulac-Sage P, Rosenbaum J.
Hepatology. 1997 Dec;26(6):1458-66.
PMID 9397985
Reconstitution of mammary gland development in vitro: requirement of c-met and c-erbB2 signaling for branching and alveolar morphogenesis.
Niemann C, Brinkmann V, Spitzer E, Hartmann G, Sachs M, Naundorf H, Birchmeier W.
J Cell Biol. 1998 Oct 19;143(2):533-45.
PMID 9786961
HGF/SF: a potent cytokine for mammary growth, morphogenesis and development.
Niranjan B, Buluwela L, Yant J, Perusinghe N, Atherton A, Phippard D, Dale T, Gusterson B, Kamalati T.
Development. 1995 Sep;121(9):2897-908.
PMID 7555716
Promyelocytic leukemia cell line, HL-60, produces human hepatocyte growth factor.
Nishino T, Kaise N, Sindo Y, Nishino N, Nishida T, Yasuda S, Masui Y.
Biochem Biophys Res Commun. 1991 Nov 27;181(1):323-30.
PMID 1720310
Gene expressions of c-met and hepatocyte growth factor in chronic liver disease and hepatocellular carcinoma.
Noguchi O, Enomoto N, Ikeda T, Kobayashi F, Marumo F, Sato C.
J Hepatol. 1996 Mar;24(3):286-92.
PMID 8778194
Expression of hepatocyte growth factor gene in endothelial and Kupffer cells of damaged rat livers, as revealed by in situ hybridization.
Noji S, Tashiro K, Koyama E, Nohno T, Ohyama K, Taniguchi S, Nakamura T.
Biochem Biophys Res Commun. 1990 Nov 30;173(1):42-7.
PMID 2147853
Adenovirus-mediated hepatocyte growth factor gene transfer prevents lethal liver failure in rats.
Nomi T, Shiota G, Isono M, Sato K, Kawasaki H.
Biochem Biophys Res Commun. 2000 Nov 19;278(2):338-43.
PMID 11097840
Hepatocyte growth factor (HGF) acts as a mesenchyme-derived morphogenic factor during fetal lung development.
Ohmichi H, Koshimizu U, Matsumoto K, Nakamura T.
Development. 1998 Apr;125(7):1315-24.
PMID 9477330
Hepatocyte growth factor (HGF) promotes oligodendrocyte progenitor cell proliferation and inhibits its differentiation during postnatal development in the rat.
Ohya W, Funakoshi H, Kurosawa T, Nakamura T.
Brain Res. 2007 May 25;1147:51-65. Epub 2007 Feb 27.
PMID 17382307
Primary structure of rat hepatocyte growth factor and induction of its mRNA during liver regeneration following hepatic injury.
Okajima A, Miyazawa K, Kitamura N.
Eur J Biochem. 1990 Oct 24;193(2):375-81.
PMID 2146117
Functional characterization of human hepatocyte growth factor mutants obtained by deletion of structural domains.
Okigaki M, Komada M, Uehara Y, Miyazawa K, Kitamura N.
Biochemistry. 1992 Oct 13;31(40):9555-61.
PMID 1327117
Overexpression and activation of hepatocyte growth factor/scatter factor in human non-small-cell lung carcinomas.
Olivero M, Rizzo M, Madeddu R, Casadio C, Pennacchietti S, Nicotra MR, Prat M, Maggi G, Arena N, Natali PG, Comoglio PM, Di Renzo MF.
Br J Cancer. 1996 Dec;74(12):1862-8.
PMID 8980383
c-Met expression of thyroid tissue with special reference to papillary carcinoma.
Oyama T, Ichimura E, Sano T, Kashiwabara K, Fukuda T, Nakajima T.
Pathol Int. 1998 Oct;48(10):763-8.
PMID 9788259
Hepatocyte growth factor in lung repair and pulmonary fibrosis.
Panganiban RA, Day RM.
Acta Pharmacol Sin. 2011 Jan;32(1):12-20. Epub 2010 Dec 6. (REVIEW)
PMID 21131996
Cell cycle effects resulting from inhibition of hepatocyte growth factor and its receptor c-Met in regenerating rat livers by RNA interference.
Paranjpe S, Bowen WC, Bell AW, Nejak-Bowen K, Luo JH, Michalopoulos GK.
Hepatology. 2007 Jun;45(6):1471-7.
PMID 17427161
Unusual proteolytic activation of pro-hepatocyte growth factor by plasma kallikrein and coagulation factor XIa.
Peek M, Moran P, Mendoza N, Wickramasinghe D, Kirchhofer D.
J Biol Chem. 2002 Dec 6;277(49):47804-9. Epub 2002 Oct 7.
PMID 12372819
Escape from Cbl-mediated downregulation: a recurrent theme for oncogenic deregulation of receptor tyrosine kinases.
Peschard P, Park M.
Cancer Cell. 2003 Jun;3(6):519-23.
PMID 12842080
Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction.
Powell EM, Campbell DB, Stanwood GD, Davis C, Noebels JL, Levitt P.
J Neurosci. 2003a Jan 15;23(2):622-31.
PMID 12533622
Differential regulation of thalamic and cortical axonal growth by hepatocyte growth factor/scatter factor.
Powell EM, Muhlfriedel S, Bolz J, Levitt P.
Dev Neurosci. 2003b Mar-Aug;25(2-4):197-206.
PMID 12966217
Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia.
Powell RJ, Simons M, Mendelsohn FO, Daniel G, Henry TD, Koga M, Morishita R, Annex BH.
Circulation. 2008 Jul 1;118(1):58-65. Epub 2008 Jun 16.
PMID 18559703
Over-expression of hepatocyte growth factor/scatter factor (HGF/SF) and the HGF/SF receptor (cMET) are associated with a high risk of metastasis and recurrence for children and young adults with papillary thyroid carcinoma.
Ramirez R, Hsu D, Patel A, Fenton C, Dinauer C, Tuttle RM, Francis GL.
Clin Endocrinol (Oxf). 2000 Nov;53(5):635-44.
PMID 11106926
The MET receptor tyrosine kinase contributes to invasive tumour growth in rhabdomyosarcomas.
Rees H, Williamson D, Papanastasiou A, Jina N, Nabarro S, Shipley J, Anderson J.
Growth Factors. 2006 Sep;24(3):197-208.
PMID 17079203
How to make tubes: signaling by the Met receptor tyrosine kinase.
Rosario M, Birchmeier W.
Trends Cell Biol. 2003 Jun;13(6):328-35. (REVIEW)
PMID 12791299
Smooth muscle releases an epithelial cell scatter factor which binds to heparin.
Rosen EM, Goldberg ID, Kacinski BM, Buckholz T, Vinter DW.
In Vitro Cell Dev Biol. 1989 Feb;25(2):163-73.
PMID 2537811
A broad-spectrum human lung fibroblast-derived mitogen is a variant of hepatocyte growth factor.
Rubin JS, Chan AM, Bottaro DP, Burgess WH, Taylor WG, Cech AC, Hirschfield DW, Wong J, Miki T, Finch PW, et al.
Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):415-9.
PMID 1824873
Dissociation of heparan sulfate and receptor binding domains of hepatocyte growth factor reveals that heparan sulfate-c-met interaction facilitates signaling.
Rubin JS, Day RM, Breckenridge D, Atabey N, Taylor WG, Stahl SJ, Wingfield PT, Kaufman JD, Schwall R, Bottaro DP.
J Biol Chem. 2001 Aug 31;276(35):32977-83. Epub 2001 Jul 2.
PMID 11435444
Detection of the c-met proto-oncogene product in normal skin and tumours of melanocytic origin.
Saitoh K, Takahashi H, Sawada N, Parsons PG.
J Pathol. 1994 Nov;174(3):191-9.
PMID 7823252
Stimulation of DNA synthesis in trophoblasts and human umbilical vein endothelial cells by hepatocyte growth factor bound to extracellular matrix.
Sakakura S, Saito S, Morikawa H.
Placenta. 1999 Nov;20(8):683-93.
PMID 10527823
Heparin binding and oligomerization of hepatocyte growth factor/scatter factor isoforms. Heparan sulfate glycosaminoglycan requirement for Met binding and signaling.
Sakata H, Stahl SJ, Taylor WG, Rosenberg JM, Sakaguchi K, Wingfield PT, Rubin JS.
J Biol Chem. 1997 Apr 4;272(14):9457-63.
PMID 9083085
Involvement of hepatocyte growth factor in kidney development.
Santos OF, Barros EJ, Yang XM, Matsumoto K, Nakamura T, Park M, Nigam SK.
Dev Biol. 1994 Jun;163(2):525-9.
PMID 8200486
Papillary carcinoma of the thyroid: evidence for a role for hepatocyte growth factor (HGF) in promoting tumour angiogenesis.
Scarpino S, D'Alena FC, Di Napoli A, Ballarini F, Prat M, Ruco LP.
J Pathol. 2003 Feb;199(2):243-50.
PMID 12533838
The role of Ito cells in the biosynthesis of HGF-SF in the liver.
Schirmacher P, Geerts A, Jung W, Pietrangelo A, Rogler CE, Dienes HP.
EXS. 1993;65:285-99. (REVIEW)
PMID 8380738
Scatter factor/hepatocyte growth factor is essential for liver development.
Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E, Birchmeier C.
Nature. 1995 Feb 23;373(6516):699-702.
PMID 7854452
Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39.
Schultz JM, Khan SN, Ahmed ZM, Riazuddin S, Waryah AM, Chhatre D, Starost MF, Ploplis B, Buckley S, Velasquez D, Kabra M, Lee K, Hassan MJ, Ali G, Ansar M, Ghosh M, Wilcox ER, Ahmad W, Merlino G, Leal SM, Riazuddin S, Friedman TB, Morell RJ.
Am J Hum Genet. 2009 Jul;85(1):25-39. Epub 2009 Jul 2.
PMID 19576567
Heparin induces dimerization and confers proliferative activity onto the hepatocyte growth factor antagonists NK1 and NK2.
Schwall RH, Chang LY, Godowski PJ, Kahn DW, Hillan KJ, Bauer KD, Zioncheck TF.
J Cell Biol. 1996 May;133(3):709-18.
PMID 8636243
High levels of soluble syndecan-1 in myeloma-derived bone marrow: modulation of hepatocyte growth factor activity.
Seidel C, Borset M, Hjertner O, Cao D, Abildgaard N, Hjorth-Hansen H, Sanderson RD, Waage A, Sundan A.
Blood. 2000 Nov 1;96(9):3139-46.
PMID 11049995
Hepatocyte growth factor in serum after injection of unfractionated and low molecular weight heparin in healthy individuals.
Seidel C, Hjorth-Hansen H, Bendz B, Borset M, Sandset PM, Hansen JB, Sundan A, Waage A.
Br J Haematol. 1999 Jun;105(3):641-7.
PMID 10354124
Isolation and expression of cDNA for different forms of hepatocyte growth factor from human leukocyte.
Seki T, Ihara I, Sugimura A, Shimonishi M, Nishizawa T, Asami O, Hagiya M, Nakamura T, Shimizu S.
Biochem Biophys Res Commun. 1990 Oct 15;172(1):321-7.
PMID 2145836
Expression of hepatocyte growth factor mRNA, and c-met mRNA (hepatocyte growth factor receptor) in human liver tumours.
Selden C, Farnaud S, Ding SF, Habib N, Foster C, Hodgson HJ.
J Hepatol. 1994 Aug;21(2):227-34.
PMID 7989714
Further characterisation of 'hepatotropin', a high molecular weight hepatotrophic factor in rat serum.
Selden C, Hodgson HJ.
J Hepatol. 1989 Sep;9(2):167-76.
PMID 2681395
Targeting of mitogen-activated protein kinases and phosphatidylinositol 3 kinase inhibits hepatocyte growth factor/scatter factor-induced angiogenesis.
Sengupta S, Sellers LA, Li RC, Gherardi E, Zhao G, Watson N, Sasisekharan R, Fan TP.
Circulation. 2003 Jun 17;107(23):2955-61. Epub 2003 Jun 2.
PMID 12782568
Transcriptional activation of the hepatocyte growth factor receptor (c-met) gene by its ligand (hepatocyte growth factor) is mediated through AP-1.
Seol DW, Chen Q, Zarnegar R.
Oncogene. 2000 Feb 24;19(9):1132-7.
PMID 10713700
Stimulation of DNA synthesis and cell proliferation of human mammary myoepithelial-like cells by hepatocyte growth factor/scatter factor depends on heparan sulfate proteoglycans and sustained phosphorylation of mitogen-activated protein kinases p42/44.
Sergeant N, Lyon M, Rudland PS, Fernig DG, Delehedde M.
J Biol Chem. 2000 Jun 2;275(22):17094-9.
PMID 10747885
Serum levels of hepatocyte growth factor in patients with breast cancer.
Sheen-Chen SM, Liu YW, Eng HL, Chou FF.
Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):715-7.
PMID 15767355
Conformational lability in serine protease active sites: structures of hepatocyte growth factor activator (HGFA) alone and with the inhibitory domain from HGFA inhibitor-1B.
Shia S, Stamos J, Kirchhofer D, Fan B, Wu J, Corpuz RT, Santell L, Lazarus RA, Eigenbrot C.
J Mol Biol. 2005 Mar 11;346(5):1335-49. Epub 2005 Jan 28.
PMID 15713485
Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia.
Shigematsu H, Yasuda K, Iwai T, Sasajima T, Ishimaru S, Ohashi Y, Yamaguchi T, Ogihara T, Morishita R.
Gene Ther. 2010 Sep;17(9):1152-61. Epub 2010 Apr 15.
PMID 20393508
Expression of hepatocyte growth factor and c-Met after spinal cord injury in rats.
Shimamura M, Sato N, Sata M, Wakayama K, Ogihara T, Morishita R.
Brain Res. 2007 Jun 2;1151:188-94. Epub 2007 Mar 13.
PMID 17425951
Hepatocyte growth factor is linked by O-glycosylated oligosaccharide on the alpha chain.
Shimizu N, Hara H, Sogabe T, Sakai H, Ihara I, Inoue H, Nakamura T, Shimizu S.
Biochem Biophys Res Commun. 1992 Dec 30;189(3):1329-35.
PMID 1482348
Hepatocyte growth factor activator inhibitor, a novel Kunitz-type serine protease inhibitor.
Shimomura T, Denda K, Kitamura A, Kawaguchi T, Kito M, Kondo J, Kagaya S, Qin L, Takata H, Miyazawa K, Kitamura N.
J Biol Chem. 1997 Mar 7;272(10):6370-6.
PMID 9045658
Hepatocyte growth factor in transgenic mice.
Shiota G, Kawasaki H.
Int J Exp Pathol. 1998 Oct;79(5):267-77. (REVIEW)
PMID 10193310
Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752.
Smolen GA, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H, Kim WJ, Okimoto RA, Bell DW, Sgroi DC, Christensen JG, Settleman J, Haber DA.
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2316-21. Epub 2006 Feb 6.
Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development.
Sonnenberg E, Meyer D, Weidner KM, Birchmeier C.
J Cell Biol. 1993 Oct;123(1):223-35.
PMID 8408200
Therapeutic targeting of human hepatocyte growth factor with a single neutralizing monoclonal antibody reduces lung tumorigenesis.
Stabile LP, Rothstein ME, Keohavong P, Jin J, Yin J, Land SR, Dacic S, Luong TM, Kim KJ, Dulak AM, Siegfried JM.
Mol Cancer Ther. 2008 Jul;7(7):1913-22.
PMID 18645002
Functional and biophysical characterization of recombinant human hepatocyte growth factor isoforms produced in Escherichia coli.
Stahl SJ, Wingfield PT, Kaufman JD, Pannell LK, Cioce V, Sakata H, Taylor WG, Rubin JS, Bottaro DP.
Biochem J. 1997 Sep 15;326 ( Pt 3):763-72.
PMID 9307026
Crystal structure of the HGF beta-chain in complex with the Sema domain of the Met receptor.
Stamos J, Lazarus RA, Yao X, Kirchhofer D, Wiesmann C.
EMBO J. 2004 Jun 16;23(12):2325-35. Epub 2004 May 27.
PMID 15167892
MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis.
Stein U, Walther W, Arlt F, Schwabe H, Smith J, Fichtner I, Birchmeier W, Schlag PM.
Nat Med. 2009 Jan;15(1):59-67. Epub 2008 Dec 21.
PMID 19098908
Epithelial scatter factor and development of the chick embryonic axis.
Stern CD, Ireland GW, Herrick SE, Gherardi E, Gray J, Perryman M, Stoker M.
Development. 1990 Dec;110(4):1271-84.
PMID 2151613
Scatter factor is a fibroblast-derived modulator of epithelial cell mobility.
Stoker M, Gherardi E, Perryman M, Gray J.
Nature. 1987 May 21-27;327(6119):239-42.
PMID 2952888
An epithelial scatter factor released by embryo fibroblasts.
Stoker M, Perryman M.
J Cell Sci. 1985 Aug;77:209-23.
PMID 3841349
Keratinocyte growth factor and fibroblast growth factor action on DNA synthesis in rat and human hepatocytes: modulation by heparin.
Strain AJ, McGuinness G, Rubin JS, Aaronson SA.
Exp Cell Res. 1994 Feb;210(2):253-9.
PMID 7507851
Preventing the loss of competence for neural induction: HGF/SF, L5 and Sox-2.
Streit A, Sockanathan S, Perez L, Rex M, Scotting PJ, Sharpe PT, Lovell-Badge R, Stern CD.
Development. 1997 Mar;124(6):1191-202.
PMID 9102306
A role for HGF/SF in neural induction and its expression in Hensen's node during gastrulation.
Streit A, Stern CD, Thery C, Ireland GW, Aparicio S, Sharpe MJ, Gherardi E.
Development. 1995 Mar;121(3):813-24.
PMID 7720585
Differential expression of hepatocyte growth factor and its receptor, c-Met in the rat retina during development.
Sun W, Funakoshi H, Nakamura T.
Brain Res. 1999 Dec 18;851(1-2):46-53.
PMID 10642827
Expression of immunoreactive human hepatocyte growth factor in human esophageal squamous cell carcinomas.
Takada N, Yano Y, Matsuda T, Otani S, Osugi H, Higashino M, Kinoshita H, Fukushima S.
Cancer Lett. 1995 Nov 6;97(2):145-8.
PMID 7497455
Loss of hepatocyte growth factor/c-Met signaling pathway accelerates early stages of N-nitrosodiethylamine induced hepatocarcinogenesis.
Takami T, Kaposi-Novak P, Uchida K, Gomez-Quiroz LE, Conner EA, Factor VM, Thorgeirsson SS.
Cancer Res. 2007 Oct 15;67(20):9844-51.
PMID 17942915
Scatter factor/hepatocyte growth factor as a regulator of skeletal muscle and neural crest development.
Takayama H, La Rochelle WJ, Anver M, Bockman DE, Merlino G.
Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5866-71.
PMID 8650184
Serum hepatocyte growth factor/scatter factor levels in small cell lung cancer patients.
Takigawa N, Segawa Y, Maeda Y, Takata I, Fujimoto N.
Lung Cancer. 1997 Jul;17(2-3):211-8.
PMID 9237156
Serum concentrations of hepatocyte growth factor in breast cancer patients.
Taniguchi T, Toi M, Inada K, Imazawa T, Yamamoto Y, Tominaga T.
Clin Cancer Res. 1995 Sep;1(9):1031-4.
PMID 9816076
Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease.
Taniyama Y, Morishita R, Aoki M, Nakagami H, Yamamoto K, Yamazaki K, Matsumoto K, Nakamura T, Kaneda Y, Ogihara T.
Gene Ther. 2001 Feb;8(3):181-9.
PMID 11313789
Validation of met as a therapeutic target in alveolar and embryonal rhabdomyosarcoma.
Taulli R, Scuoppo C, Bersani F, Accornero P, Forni PE, Miretti S, Grinza A, Allegra P, Schmitt-Ney M, Crepaldi T, Ponzetto C.
Cancer Res. 2006 May 1;66(9):4742-9.
PMID 16651427
Hepatopoietin A: partial characterization and trypsin activation of a hepatocyte growth factor.
Thaler FJ, Michalopoulos GK.
Cancer Res. 1985 Jun;45(6):2545-9.
PMID 3157446
The expression of mRNAs for hepatocyte growth factor/scatter factor, its receptor c-met, and one of its activators tissue-type plasminogen activator show a systematic relationship in the developing and adult cerebral cortex and hippocampus.
Thewke DP, Seeds NW.
Brain Res. 1999 Mar 13;821(2):356-67.
PMID 10064822
Hepatic growth factor (HGF) inhibits cigarette smoke extract induced apoptosis in human bronchial epithelial cells.
Togo S, Sugiura H, Nelson A, Kobayashi T, Wang X, Kamio K, Kawasaki S, Bitterman P, Rennard SI, Liu X.
Exp Cell Res. 2010 Dec 10;316(20):3501-11. Epub 2010 Sep 17.
PMID 20850432
Significance of circulating hepatocyte growth factor level as a prognostic indicator in primary breast cancer.
Toi M, Taniguchi T, Ueno T, Asano M, Funata N, Sekiguchi K, Iwanari H, Tominaga T.
Clin Cancer Res. 1998 Mar;4(3):659-64.
PMID 9533534
A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist.
Tolbert WD, Daugherty J, Gao C, Xie Q, Miranti C, Gherardi E, Woude GV, Xu HE.
Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14592-7. Epub 2007 Sep 5.
PMID 17804794
Overexpression of hepatocyte growth factor/scatter factor promotes vascularization and granulation tissue formation in vivo.
Toyoda M, Takayama H, Horiguchi N, Otsuka T, Fukusato T, Merlino G, Takagi H, Mori M.
FEBS Lett. 2001 Nov 30;509(1):95-100.
PMID 11734213
Expression of the hepatocyte growth factor and c-met in normal thyroid, non-neoplastic, and neoplastic nodules.
Trovato M, Villari D, Bartolone L, Spinella S, Simone A, Violi MA, Trimarchi F, Batolo D, Benvenga S.
Thyroid. 1998 Feb;8(2):125-31.
PMID 9510120
Hepatocyte growth factor is predominantly expressed by the carcinoma cells in non-small-cell lung cancer.
Tsao MS, Yang Y, Marcus A, Liu N, Mou L.
Hum Pathol. 2001 Jan;32(1):57-65.
PMID 11172296
Hepatocyte growth factor/scatter factor is an autocrine factor for human normal bronchial epithelial and lung carcinoma cells.
Tsao MS, Zhu H, Giaid A, Viallet J, Nakamura T, Park M.
Cell Growth Differ. 1993 Jul;4(7):571-9.
PMID 8398897
Immunohistochemical localization of hepatocyte growth factor protein in pancreas islet A-cells of man and rats.
Tsuda H, Iwase T, Matsumoto K, Ito M, Hirono I, Nishida Y, Yamamoto M, Tatematsu M, Matsumoto K, Nakamura T.
Jpn J Cancer Res. 1992 Dec;83(12):1262-6.
PMID 1362429
Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor.
Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T, Kitamura N.
Nature. 1995 Feb 23;373(6516):702-5.
PMID 7854453
Expression of hepatocyte growth factor and its receptor, the c-met proto-oncogene, in hepatocellular carcinoma.
Ueki T, Fujimoto J, Suzuki T, Yamamoto H, Okamoto E.
Hepatology. 1997 Mar;25(3):619-23.
PMID 9049208
Crystal structure of the NK1 fragment of human hepatocyte growth factor at 2.0 A resolution.
Ultsch M, Lokker NA, Godowski PJ, de Vos AM.
Structure. 1998 Nov 15;6(11):1383-93.
PMID 9817840
Potentiated angiogenic effect of scatter factor/hepatocyte growth factor via induction of vascular endothelial growth factor: the case for paracrine amplification of angiogenesis.
Van Belle E, Witzenbichler B, Chen D, Silver M, Chang L, Schwall R, Isner JM.
Circulation. 1998 Feb 3;97(4):381-90.
PMID 9468212
Association between serum hepatocyte growth factor and survival in untreated hepatocellular carcinoma.
Vejchapipat P, Tangkijvanich P, Theamboonlers A, Chongsrisawat V, Chittmittrapap S, Poovorawan Y.
J Gastroenterol. 2004 Dec;39(12):1182-8.
PMID 15622483
The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression.
Verras M, Lee J, Xue H, Li TH, Wang Y, Sun Z.
Cancer Res. 2007 Feb 1;67(3):967-75.
PMID 17283128
Pathways to melanoma development: lessons from the mouse.
Walker GJ, Hayward NK.
J Invest Dermatol. 2002 Oct;119(4):783-92. (REVIEW)
PMID 12406321
A new crystal form of the NK1 splice variant of HGF/SF demonstrates extensive hinge movement and suggests that the NK1 dimer originates by domain swapping.
Watanabe K, Chirgadze DY, Lietha D, de Jonge H, Blundell TL, Gherardi E.
J Mol Biol. 2002 May 31;319(2):283-8.
PMID 12051906
The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells.
Weidner KM, Sachs M, Birchmeier W.
J Cell Biol. 1993 Apr;121(1):145-54.
PMID 8384622
A phase II study evaluating the efficacy and safety of AMG 102 (rilotumumab) in patients with recurrent glioblastoma.
Wen PY, Schiff D, Cloughesy TF, Raizer JJ, Laterra J, Smitt M, Wolf M, Oliner KS, Anderson A, Zhu M, Loh E, Reardon DA.
Neuro Oncol. 2011 Apr;13(4):437-46. Epub 2011 Feb 4.
PMID 21297127
Microscopic analysis of the cellular events during scatter factor/hepatocyte growth factor-induced epithelial tubulogenesis.
Williams MJ, Clark P.
J Anat. 2003 Nov;203(5):483-503.
PMID 14635802
Hepatocyte growth factor increases expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 in human keratinocytes and the vascular endothelial growth factor receptor flk-1 in human endothelial cells.
Wojta J, Kaun C, Breuss JM, Koshelnick Y, Beckmann R, Hattey E, Mildner M, Weninger W, Nakamura T, Tschachler E, Binder BR.
Lab Invest. 1999 Apr;79(4):427-38.
PMID 10211995
Hepatocyte growth factor in human placenta and trophoblastic disease.
Wolf HK, Zarnegar R, Oliver L, Michalopoulos GK.
Am J Pathol. 1991 Apr;138(4):1035-43.
PMID 1849357
Hepatocyte growth factor promotes motor neuron survival and synergizes with ciliary neurotrophic factor.
Wong V, Glass DJ, Arriaga R, Yancopoulos GD, Lindsay RM, Conn G.
J Biol Chem. 1997 Feb 21;272(8):5187-91.
PMID 9030587
Roles of hepatocyte growth factor/scatter factor and the met receptor in the early development of the metanephros.
Woolf AS, Kolatsi-Joannou M, Hardman P, Andermarcher E, Moorby C, Fine LG, Jat PS, Noble MD, Gherardi E.
J Cell Biol. 1995 Jan;128(1-2):171-84.
PMID 7822413
Hepatocyte growth factor enhances vascular endothelial growth factor-induced angiogenesis in vitro and in vivo.
Xin X, Yang S, Ingle G, Zlot C, Rangell L, Kowalski J, Schwall R, Ferrara N, Gerritsen ME.
Am J Pathol. 2001 Mar;158(3):1111-20.
PMID 11238059
Serum concentrations of human hepatocyte growth factor is a useful indicator for predicting the occurrence of hepatocellular carcinomas in C-viral chronic liver diseases.
Yamagamim H, Moriyama M, Matsumura H, Aoki H, Shimizu T, Saito T, Kaneko M, Shioda A, Tanaka N, Arakawa Y.
Cancer. 2002 Aug 15;95(4):824-34.
PMID 12209727
Hepatocyte growth factor specifically expressed in microglia activated Ras in the neurons, similar to the action of neurotrophic factors.
Yamagata T, Muroya K, Mukasa T, Igarashi H, Momoi M, Tsukahara T, Arahata K, Kumagai H, Momoi T.
Biochem Biophys Res Commun. 1995 May 5;210(1):231-7.
PMID 7537964
Hepatocyte growth factor (HGF/SF) is a muscle-derived survival factor for a subpopulation of embryonic motoneurons.
Yamamoto Y, Livet J, Pollock RA, Garces A, Arce V, deLapeyriere O, Henderson CE.
Development. 1997 Aug;124(15):2903-13.
PMID 9247333
High levels of hepatocyte growth factor/scatter factor in diffuse-type bronchioloalveolar cell carcinoma.
Yamashita J, Ogawa M, Nakano S, Okabe K, Abe M, Iwasaki A, Kuwahara M, Yoshinaga Y, Shirakusa T.
Cancer. 1998 Nov 15;83(10):2091-8.
PMID 9827713
Hepatocyte growth factor may act as a pulmotrophic factor on lung regeneration after acute lung injury.
Yanagita K, Matsumoto K, Sekiguchi K, Ishibashi H, Niho Y, Nakamura T.
J Biol Chem. 1993 Oct 5;268(28):21212-7.
PMID 8407957
Expression of the met/hepatocyte growth factor/scatter factor receptor and its ligand during differentiation of murine P19 embryonal carcinoma cells.
Yang XM, Park M.
Dev Biol. 1993 Jun;157(2):308-20.
PMID 8388815
Sequential requirement of hepatocyte growth factor and neuregulin in the morphogenesis and differentiation of the mammary gland.
Yang Y, Spitzer E, Meyer D, Sachs M, Niemann C, Hartmann G, Weidner KM, Birchmeier C, Birchmeier W.
J Cell Biol. 1995 Oct;131(1):215-26.
PMID 7559778
In vivo effects of hepatocyte growth factor/scatter factor on mouse mammary gland development.
Yant J, Buluwela L, Niranjan B, Gusterson B, Kamalati T.
Exp Cell Res. 1998 Jun 15;241(2):476-81.
PMID 9637789
Actions of hepatocyte growth factor as a local modulator in the kidney: potential role in pathogenesis of renal disease.
Yo Y, Morishita R, Yamamoto K, Tomita N, Kida I, Hayashi S, Moriguchi A, Kato S, Matsumoto K, Nakamura T, Higaki J, Ogihara T.
Kidney Int. 1998 Jan;53(1):50-8.
PMID 9452999
Neutralization of hepatocyte growth factor leads to retarded cutaneous wound healing associated with decreased neovascularization and granulation tissue formation.
Yoshida S, Yamaguchi Y, Itami S, Yoshikawa K, Tabata Y, Matsumoto K, Nakamura T.
J Invest Dermatol. 2003 Feb;120(2):335-43.
PMID 12542542
Tissue distribution of hepatopoietin-A: a heparin-binding polypeptide growth factor for hepatocytes.
Zarnegar R, Muga S, Rahija R, Michalopoulos G.
Proc Natl Acad Sci U S A. 1990 Feb;87(3):1252-6.
PMID 2137248
MET kinase inhibitor SGX523 synergizes with epidermal growth factor receptor inhibitor erlotinib in a hepatocyte growth factor-dependent fashion to suppress carcinoma growth.
Zhang YW, Staal B, Essenburg C, Su Y, Kang L, West R, Kaufman D, Dekoning T, Eagleson B, Buchanan SG, Vande Woude GF.
Cancer Res. 2010 Sep 1;70(17):6880-90. Epub 2010 Jul 19.
PMID 20643778
Identification and dynamics of a heparin-binding site in hepatocyte growth factor.
Zhou H, Casas-Finet JR, Heath Coats R, Kaufman JD, Stahl SJ, Wingfield PT, Rubin JS, Bottaro DP, Byrd RA.
Biochemistry. 1999 Nov 9;38(45):14793-802.
PMID 10555961
The solution structure of the N-terminal domain of hepatocyte growth factor reveals a potential heparin-binding site.
Zhou H, Mazzulla MJ, Kaufman JD, Stahl SJ, Wingfield PT, Rubin JS, Bottaro DP, Byrd RA.
Structure. 1998 Jan 15;6(1):109-16.
PMID 9493272
Sulfated oligosaccharides promote hepatocyte growth factor association and govern its mitogenic activity.
Zioncheck TF, Richardson L, Liu J, Chang L, King KL, Bennett GL, Fugedi P, Chamow SM, Schwall RH, Stack RJ.
J Biol Chem. 1995 Jul 14;270(28):16871-8.
PMID 7622503
An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms.
Zou HY, Li Q, Lee JH, Arango ME, McDonnell SR, Yamazaki S, Koudriakova TB, Alton G, Cui JJ, Kung PP, Nambu MD, Los G, Bender SL, Mroczkowski B, Christensen JG.
Cancer Res. 2007 May 1;67(9):4408-17.
PMID 17483355
Met overexpression confers HGF-dependent invasive phenotype to human thyroid carcinoma cells in vitro.
de Luca A, Arena N, Sena LM, Medico E.
J Cell Physiol. 1999 Sep;180(3):365-71.
PMID 10430176


This paper should be referenced as such :
Athauda, G ; Cecchi, F ; Ito, T ; Giubellino, A ; Rabe, D ; Raffensperger, K ; Lee, Y ; Bottaro, DP
HGF (hepatocyte growth factor (hepapoietin A; scatter factor))
Atlas Genet Cytogenet Oncol Haematol. 2011;15(12):1008-1025.
Free journal version : [ pdf ]   [ DOI ]

External links

HGNC (Hugo)HGF   4893
Atlas Explorer : (Salamanque)HGF
Entrez_Gene (NCBI)HGF    hepatocyte growth factor
AliasesDFNB39; F-TCF; HGFB; HPTA; 
GeneCards (Weizmann)HGF
Ensembl hg19 (Hinxton)ENSG00000019991 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000019991 [Gene_View]  ENSG00000019991 [Sequence]  chr7:81750900-81770047 [Contig_View]  HGF [Vega]
ICGC DataPortalENSG00000019991
TCGA cBioPortalHGF
Genatlas (Paris)HGF
SOURCE (Princeton)HGF
Genetics Home Reference (NIH)HGF
Genomic and cartography
GoldenPath hg38 (UCSC)HGF  -     chr7:81750900-81770047 -  7q21.11   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)HGF  -     7q21.11   [Description]    (hg19-Feb_2009)
GoldenPathHGF - 7q21.11 [CytoView hg19]  HGF - 7q21.11 [CytoView hg38]
Genome Data Viewer NCBIHGF [Mapview hg19]  
OMIM142409   608265   
Gene and transcription
Genbank (Entrez)AB208900 AK291674 AK313694 AV701693 BC022308
RefSeq transcript (Entrez)NM_000601 NM_001010931 NM_001010932 NM_001010933 NM_001010934
Consensus coding sequences : CCDS (NCBI)HGF
Gene ExpressionHGF [ NCBI-GEO ]   HGF [ EBI - ARRAY_EXPRESS ]   HGF [ SEEK ]   HGF [ MEM ]
Gene Expression Viewer (FireBrowse)HGF [ Firebrowse - Broad ]
GenevisibleExpression of HGF in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3082
GTEX Portal (Tissue expression)HGF
Human Protein AtlasENSG00000019991-HGF [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)HGF
Human Protein Atlas [tissue]ENSG00000019991-HGF [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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