MST1 (macrophage stimulating 1 (hepatocyte growth factor-like))

2013-05-01   Makiko Kawaguchi , Hiroaki Kataoka 

Section of Oncopathology, Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan

Identity

HGNC
LOCATION
3p21.31
LOCUSID
ALIAS
D3F15S2,DNF15S2,HGFL,MSP,NF15S2
FUSION GENES

DNA/RNA

Atlas Image
Structure of the human MST1 gene.

Description

Total length: 4817 bp; mRNA product length: 2348 bp.

Transcription

The human MST1 gene structure consists of 18 exons and 17 introns spanning 4817 bp. One transcript of 2348 bps mRNA encode for 711 amino acid.

Pseudogene

There are no known pseudogenes.

Proteins

Note

MSP was originally identified by E.J. Leonard as a serum protein that activates murine resident peritoneal macrophages (Skeel et al., 1991). The specific receptor for MSP is recepteur dorigine nantais (RON) tyrosine kinase, a member of the MET proto-oncogene family (Wang et al., 2002).
Atlas Image
Schematic representations of the domain structures of pro-MSP and mature MSP proteins. After proteolytic cleavage at the Arg483-Val484 bond, pro-MSP is converted to mature MSP and acquires its biological activity. Mature MSP is composed of α-chain (53 kDa) and β-chain (30 kDa) linked by a disulfide bond. The α-chain contains PAN/APPLE-like domain, followed by four kringle domains, and the β-chain has a serine protease (peptidase S1)-like domain. SP, signal peptide; PAN, PAN/APPLE-like domain; K1-K4, Kringle domain1-4.

Description

The human MSP has the highest amino acid sequence similarity (45%) to human hepatocyte growth factor (HGF), hence its name "hepatocyte growth factor-like protein (HGFL)". MSP is a glycoprotein belonging to a plasminogen-related growth factor family. It is secreted as a single-chain precursor protein (pro-MSP), which has no biological activity (Wang et al., 2002). Pro-MSP becomes active after cleavage at the Arg483-Val484 bond by specific trypsin-like serine proteases such as hepatocyte growth factor activator (HGFA), ST14 (matriptase), hepsin (transmembrane protease, serine 1; TMPRSS1), TMPRSS11D (Human airway trypsin-like protease; HAT), clotting factor XIIa, clotting factor XIa, and serum kallikrein (Wang et al., 2002; Kawaguchi et al., 2009; Bhatt et al., 2007; Ganesan et al., 2011; Orikawa et al., 2012). Among them, HGFA is a physiological serum activator of MSP at site of tissue injury, and ST14/matriptase likely has significant roles in activation of MSP/RON signaling on the cell surface as a cellular activator. In respiratory epithelial cells, TMPRSS11D/HAT serves as an efficient activator of MSP. In addition, hepsin may have a role in cancer cells. After cleavage of pro-MSP, MSP β-chain binds to its specific receptor tyrosine kinase RON, which results in autophosphorylation within its kinase catalytic domain, leading to the initiation of multiple signaling pathways including Ras/mitogen-activated protein kinase, phosphatidylinositol 3-kinase, c-Jun amino terminal kinase, β-catenin and nuclear factor-kappaB (NF-κB) (Wang et al., 2002; Kretschmann et al., 2010).

Expression

MSP transcripts are present in the liver and, to a lesser amount, in adrenal glands, lungs, kidney, placenta and pancreas (Yoshimura et al., 1993; Ganesan et al., 2011).

Localisation

MSP is synthesized and secreted mainly by hepatocytes as a biologically inactive single-chain precursor form and circulate as a plasma protein. The concentration of pro-MSP in the plasma is about 2-5 nM (Wang et al., 2002). Pro-MSP is activated by trypsin-like serum serine proteases such as HGFA, clotting factor XIIa, clotting factor XIa, serum kallikrein. On the cell surface, this activation can be processed by membrane-anchored serine proteases such as ST14/matriptase, hepsin and TMPRSS11D/HAT.

Function

MSP was originally identified as a serum protein that activates resident macrophages, such as induction of shape change and motility, enhanced chemotaxis in response to complement factor C5a (Wang et al., 2002). However, its biological effects are not restricted to macrophages. MSP promotes proliferation and migration of various epithelial cells and microglia (Kretschmann et al., 2010; Suzuki et al., 2008), increases ciliary motility of nasal epithelial cells (Sakamoto et al., 1997), stimulates the bone resorbing activity of osteoclasts (Kurihara et al., 1996), and stimulates sperm motility (Ohshiro et al., 1996). To date, many studies have suggested that MSP/RON signaling pathway plays roles in various pathophysiological conditions such as inflammation, wound healing, and cancer. Gene knockout studies revealed that MSP is not essential for embryogenesis, fertility (Bezerra et al., 1998).

Inflammation
During inflammation, MSP exerts a dual function, both stimulatory and inhibitory, on macrophages. Stimulatory functions include its ability to induce macrophage spreading, migration, phagocytosis and the production of cytokines. However, MSP inhibits lipopolysaccharide-induced production of inflammatory mediators, such as inducible NO synthase, cyclooxygenase-2, and prostaglandin E2. These suppressive effects are mediated by RON-transduced signals that block LPS-induced activation of NF-κB pathways (Wang et al., 2002; Kretschmann et al., 2010).

Wound healing
MSP/RON signaling is involved at various steps of wound healing process. MSP promotes keratinocyte migration in mouse wound models and in wound healing assays in vitro. In experimental excisional wounds in rats, expression levels of MSP and RON within the wound were highest between 7 and 21 days. In a lung injury model, the function of MSP/RON appears to be necessary to suppress NF-κB activation and RON deficient mice exhibited increased lung injury and significantly decreased survival times (Kretschmann et al., 2010). However, MSP deficient mice do not show any defects in a skin wound healing model, suggesting that functional redundancies exist in the wound healing process (Bezerra et al., 1998). In a gentamicin(GM)-induced nephropathy model, MSP attenuates GM-induced inflammation and apoptosis by inhibition of the MAPKs/NF-κB signaling pathways (Lee et al., 2013).

Homology

The human MSP has 45% amino acid sequence identity to hepatocyte growth factor, 43% to plasminogen and 36% to prothrombin, and 79% identity with murine and rat orthologue.

Mutations

Note

Non-synonymous SNP (rs3197999, R689C) in the human MST-1 gene has been linked to inflammatory bowel disease (IBD) (Goyette et al., 2008; Latiano et al., 2010). This R689C variant impairs MSP function by reducing its affinity to RON. Recent study suggests that the rs3197999 variant in MST1 gene is also associated with primary sclerosing cholangitis (PSC) and extrahepatic cholangiocarcinoma (Melum et al., 2011; Srivastava et al., 2012; Krawczyk et al., 2013).

Implicated in

Entity name
Cancer
Note
Activation of RON by MSP can initiate signaling through many pathways implicated in tumor progression and metastasis. MSP activating serine proteases, such as HGFA, ST14/matriptase and hepsin are upregulated in various cancers. In addition, RON is overexpressed in many types of epithelial cancer. When MSP was activated at sites of tumors it would not only lead to activation of RON on tumor-associated macrophages, but also on the tumor cells, where RON has been shown to induce proliferation, survival, cell migration, epithelial-mesenchymal transition (EMT), invasion and metastasis. Furthermore, MSP/RON regulates M2 macrophage polarization leading to secretion of immunosuppressive cytokines as well as growth and angiogenic factors that promote the tumor progression. (Kretschmann et al., 2010).
Entity name
Lung cancer
Note
MSP promoted liver metastasis of small cell lung cancer cells in a mouse model. Moreover, immunohistochemical analyses of liver metastases revealed that microvessel density and tumor-associated macrophages are significantly increased in lesions produced by MSP transfected cells (Sato et al., 2013).
Entity name
Breast cancer
Note
In the MMTV-PyMT mouse breast cancer model, MSP promoted tumor growth and increased metastatic frequency. The most prominent effect of MSP expression in tumors was osteolytic metastasis to bone (Welm et al., 2007). Immunohistochemical analysis revealed that the proportion of malignant tumors (invasive ductal carcinoma) positive for MSP expression was significantly higher than that of benign tumor (Ren et al., 2012). However, there was no relationship between MSP expression and histopathological grade of the carcinoma cells.
Prognosis
Breast cancer patients whose tumor overexpressed MSP/ST14/RON had significantly shorter metastasis-free survival and overall survival compared with patients whose tumors did not overexpress MSP/ST14/RON genes. Furthermore, overexpression of MSP/ST14/RON increased incidence of bone, lung, liver and brain metastases (Welm et al., 2007).
Entity name
Pancreatic cancer
Note
MSP-induced activation of RON leads to enhanced L3.6pl pancreatic cancer cell migration and invasion. RON activation also induced morphological spindle-shape change and altered expression of E-cadherin (Camp et al., 2007). MSP strongly induced phosphorylation and nuclear translocation of ribosomal S6 kinases (RSK)-2, a downstream signaling protein of the Ras-Erk1/2 pathway. RSK-2 expressing L3.6pl pancreatic cancer cell shows EMT-like phenotypic changes after MSP stimulation (Ma et al., 2011).
Entity name
Merkel cell carcinoma
Note
Tissue samples from 14 cases of Merkel cell carcinoma were used for immunohistochemical analysis. Nine cases out of 14 were positive for MSP and 9 cases out of 14 cases were positive for RON. Normal Merkel cells were negative for MSP and RON, suggesting MSP/RON signaling could play a role in tumorigenesis of MCC (Nagahama et al., 2011).
Entity name
Knee osteoarthritis (OA)
Note
By using glycoproteomic approach, MSP was found as a prognostic factor for knee OA (Fukuda et al., 2012). In situ hybridization confirmed that abundant MSP mRNA expression was observed in the synovial tissues from OA knee.
Prognosis
Higher plasma MSP level was associated with the progression of knee OA.

Bibliography

Pubmed IDLast YearTitleAuthors
94869891998Biological effects of targeted inactivation of hepatocyte growth factor-like protein in mice.Bezerra JA et al
173894012007Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway.Bhatt AS et al
173113082007Tyrosine kinase receptor RON in human pancreatic cancer: expression, function, and validation as a target.Camp ER et al
219316482011Genetic evidence supporting the association of protease and protease inhibitor genes with inflammatory bowel disease: a systematic review.Cleynen I et al
226727592012Potential plasma biomarkers for progression of knee osteoarthritis using glycoproteomic analysis coupled with a 2D-LC-MALDI system.Fukuda I et al
218759332011Proteolytic activation of pro-macrophage-stimulating protein by hepsin.Ganesan R et al
190791702008Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis.Goyette P et al
194568602009Hepatocyte growth factor activator is a serum activator of single-chain precursor macrophage-stimulating protein.Kawaguchi M et al
234220302013Macrophage stimulating protein variation enhances the risk of sporadic extrahepatic cholangiocarcinoma.Krawczyk M et al
205456052010The macrophage stimulating protein/Ron pathway as a potential therapeutic target to impede multiple mechanisms involved in breast cancer progression.Kretschmann KL et al
86116951996Macrophage-stimulating protein activates STK receptor tyrosine kinase on osteoclasts and facilitates bone resorption by osteoclast-like cells.Kurihara N et al
200249042010Variants at the 3p21 locus influence susceptibility and phenotype both in adults and early-onset patients with inflammatory bowel disease.Latiano A et al
235833942013Macrophage-stimulating protein attenuates gentamicin-induced inflammation and apoptosis in human renal proximal tubular epithelial cells.Lee KE et al
216196832011Ribosomal protein S6 kinase (RSK)-2 as a central effector molecule in RON receptor tyrosine kinase mediated epithelial to mesenchymal transition induced by macrophage-stimulating protein.Ma Q et al
211511272011Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci.Melum E et al
217230472011Tyrosine kinase receptor RON and its ligand MSP in Merkel cell carcinoma.Nagahama J et al
88581361996Molecular cloning of rat macrophage-stimulating protein and its involvement in the male reproductive system.Ohshiro K et al
222451542012Activation of macrophage-stimulating protein by human airway trypsin-like protease.Orikawa H et al
118567682002Macrophage-stimulating protein is produced by tubular cells and activates mesangial cells.Rampino T et al
225152902012Expression and mutational status of RON in neoplastic lesions of the breast: analysis of MSP/RON signaling in ductal carcinoma in situ and invasive ductal carcinoma.Ren X et al
90458731997Role of macrophage-stimulating protein and its receptor, RON tyrosine kinase, in ciliary motility.Sakamoto O et al
230116772013Macrophage stimulating protein promotes liver metastases of small cell lung cancer cells by affecting the organ microenvironment.Sato S et al
218106042011Regulation of macrophage arginase expression and tumor growth by the Ron receptor tyrosine kinase.Sharda DR et al
18271411991Macrophage stimulating protein: purification, partial amino acid sequence, and cellular activity.Skeel A et al
225541932012Fine mapping and replication of genetic risk loci in primary sclerosing cholangitis.Srivastava B et al
184805482008Regulation of cell migration and cytokine production by HGF-like protein (HLP) / macrophage stimulating protein (MSP) in primary microglia.Suzuki Y et al
124726652002Macrophage-stimulating protein and RON receptor tyrosine kinase: potential regulators of macrophage inflammatory activities.Wang MH et al
174565942007The macrophage-stimulating protein pathway promotes metastasis in a mouse model for breast cancer and predicts poor prognosis in humans.Welm AL et al
83934431993Cloning, sequencing, and expression of human macrophage stimulating protein (MSP, MST1) confirms MSP as a member of the family of kringle proteins and locates the MSP gene on chromosome 3.Yoshimura T et al

Other Information

Locus ID:

NCBI: 4485
MIM: 142408
HGNC: 7380
Ensembl: ENSG00000173531

Variants:

dbSNP: 4485
ClinVar: 4485
TCGA: ENSG00000173531
COSMIC: MST1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000173531ENST00000448220H7C0F8
ENSG00000173531ENST00000449682G3XAK1

Expression (GTEx)

0
50
100
150
200
250
300
350
400

Pathways

PathwaySourceExternal ID
Signal TransductionREACTOMER-HSA-162582
Signaling by MST1REACTOMER-HSA-8852405

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
184384062008Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease.134
129196772003The MSP receptor regulates alpha6beta4 and alpha3beta1 integrins via 14-3-3 proteins in keratinocyte migration.73
199446972010Genome-wide association analysis in primary sclerosing cholangitis.73
174565942007The macrophage-stimulating protein pathway promotes metastasis in a mouse model for breast cancer and predicts poor prognosis in humans.64
200140192010Genome wide association (GWA) predictors of anti-TNFalpha therapeutic responsiveness in pediatric inflammatory bowel disease.41
161703492006Repression of the MSP/MST-1 gene contributes to the antiapoptotic gain of function of mutant p53.28
190791702008Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis.28
218759332011Proteolytic activation of pro-macrophage-stimulating protein by hepsin.19
239287322013Mst1 overexpression inhibited the growth of human non-small cell lung cancer in vitro and in vivo.19
212491502011Cross-regulation between oncogenic BRAF(V600E) kinase and the MST1 pathway in papillary thyroid carcinoma.18

Citation

Makiko Kawaguchi ; Hiroaki Kataoka

MST1 (macrophage stimulating 1 (hepatocyte growth factor-like))

Atlas Genet Cytogenet Oncol Haematol. 2013-05-01

Online version: http://atlasgeneticsoncology.org/gene/44411/mst1