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S100A4 (S100 Calcium Binding Protein A4)

Written2011-03Gajanan V Sherbet
School of Electrical, Electronic, Computer Engineering, University of Newcastle upon Tyne, UK, Institute for Molecular Medicine, Huntington Beach, CA, USA
Updated2013-11Gajanan V Sherbet
School of Electrical, Electronic, Computer Engineering, University of Newcastle upon Tyne, UK, Institute for Molecular Medicine, Huntington Beach, CA, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesMTS1
CAPL
S100 calcium-binding protein A4 (calcium protein, calvasculin, metastasin, murine placental homolog)
S100 calcium binding protein A4 (calcium protein, calvasculin, metastasin, murine placental homolog)
Alias_symbol (synonym)P9KA
18A2
PEL98
42A
FSP1
HGNC (Hugo) S100A4
LocusID (NCBI) 6275
Atlas_Id 42192
Location 1q21.3  [Link to chromosome band 1q21]
Location_base_pair Starts at 153516098 and ends at 153518282 bp from pter ( according to hg19-Feb_2009)  [Mapping S100A4.png]
Local_order The 1q21 locus harbours the epidermal differentiation complex (EDC) encompassing a 2.05 Mbp of human genomic DNA. The S100 family genes except the S100beta are arranged in the following order: 1 cen-S100A10-S100A11-THH (trychohyalin)-FLG (filaggrin)-IVL (involucrin)-LOR (loricrin)-S100A9-S100A12-S100A8-S100A7A-S100A7P1-S100A7L2-S100A7P2-S100A7-S100A6-S100A5-S100A4-S100A3-S100A2-S100A16-S100A14-S100A13-S100A1-1qtel. S100beta is located on 21q22.3 (Schäfer et al., 1995; Marenholz et al., 1996; Mischke et al., 1996; GeneLoc version 2.41: pseudogenes S100A7P1: HGNC 21654 , S100A7P2: HGNC 21656). S100A11 pseudogenes have been listed (Pseudogenes.org); they are not shown here.
The 18A2 cDNA/mRNA (S100A4) was cloned and its structure, translation product and tissue distribution were described by Jackson-Grusby and colleagues. The sequence of 18A2 was similar to that of the 2A9 clone described by Calabretta and collegues.
 
  Figure 1. A. Chromosome 1 ideogram showing the location of S100A4 based on National Library of Medicine Handbook. B. The position of S100A4 is based on Entrez Gene ID 6275 (not drawn to scale).
Fusion genes
(updated 2016)
GTF2F2 (13q14.12) / S100A4 (1q21.3)S100A4 (1q21.3) / CLK1 (2q33.1)S100A4 (1q21.3) / SDCBP2 (20p13)

DNA/RNA

Note Starts 153516089 bp from pter; ends 153522612 bp from pter; 6524 bases; orientation minus strand.
Homo sapiens chromosome 1, GRCh37 primary reference assembly.
NCBI reference sequence: NC_000001.10, NT_004487.19.
 
  Figure 2. Based on USCS GRCh37/hg19 Feb. 2009. Not drawn to scale.
Description The human S100A4 gene has four exons. Exon 1 is non-coding and exons 2 and 3 are coding exons. Exon 2 with the start codon and encodes N-terminal EF hand and exon 3 encodes the C-terminal EF-hand. The fourth non-coding exon occurs in the 5'-UTR.
Transcription Two variant RNA transcripts from Source Search. The NM_019554 is a longer transcript. NM_002961 possesses alternate 5'-UTR; both encode the same protein isoform.
NCBI reference sequence NM_019554 ver 01954.2 564 bp mRNA; NM 002961 ver 002961.2; 512 bp mRNA.
Splice variants have been reported of S100A4. In human osteosarcoma, alternative splicing within the 5'-untranslated region (UTR) generates the two variants. Both variants, hu-mts1 and hu-mts1 (var), contain one open reading frame, differ slightly in translational capacity; possess similar stability. The hu-mts1 and hu-mts1 (var) splice variants with exons 1, 2, 3, and 4 and another with exons 1, 3 and 4, may be differentially expressed. The hu-mts1 (var) is expressed in the colon but not in the liver; it was not found in leukocytes, neutrophils, macrophages and lymphocytes. The hu-mts1 variant predominated in human breast carcinoma (SK-BR-3) and lung carcinoma (A549) is predominant (Ambartsumian et al., 1995). The differential association of the variants has been described in gastric cancers, which seems to relate to disease state possibly relates to progression; however the expression status of the variants in the lymph node metastases is not known. A splice transcript with loss of non-coding exon 1a/1b, but exons 2 and 3 present has been described in infiltrating carcinoma of the breast by Albertazzi et al. One would note nonetheless that Alternative Splicing and Transcript Diversity (ASTD) have listed 12 variant transcripts.

Regulation of transcription
Binding sites for several transcription factors have been identified in the promoter of S100A4. SABiosciences ChIP-qPCR Assay database lists 19 p53 binding sites.
Multiple NFAT (nuclear factor of activated T cells) transcription factor consensus binding sites; NF-kappaB related binding site (Tulchinsky et al., 1997). Much evidence is also available regarding activation of NF-kappaB by S100A4. S100A4 can activate NF-kappaB via the classical pathway mediated by MEKK/IKKβ; S100A6 and S100P also are capable of exerting pro-metastatic effects again by activating the NF-kappaB pathway. Experimentally induced expression of S100A4 is inhibited by NF-kappaB inhibitors. Aside from these, several other regulatory pathways may be identified, e.g. the Wnt/β-catenin/TCF, HIF/HER among others, as evidenced by the established phenotypic expression induced by the gene.
S100A4 has been postulated to signal via RAGE (receptor for advanced glycation end products) which is known to activate NF-kappaB.
A composite enhancer consisting of 6 cis-elements has been identified in the first intron of murine S100A4. This interacts with Sp1 and AP-1 family members and CBF (core binding factor alpha) and KRC (zinc finger transcription factor kappa recognition component) transcription factors.

Pseudogene None reported.

Protein

 
  Figure 3. Sequence.
Description Human S100A4 (also mouse and rat S100A4) contains 101 aminoacid residues and is approx 12 kDa in size. In common with most S100 family members, S100A4 is an antiparallel homodimer stabilised by noncovalent interactions between two helices from each subunit forming an X-type four-helix bundle. Each subunit has two calcium-binding EF-hands linked by the intermediate hinge region and a distinctive C-terminal extension. A pseudo-EF hand formed by helices 1 and 2 and the pseudo-EF-hand and a canonical EF-hand that are brought into proximity by a small two-stranded antiparallel beta-sheet. The hinge region and the C-terminal loop of S100 proteins are involved in target protein binding. Calcium binding produces a conformational change, which leads to the exposure of hydrophobic pocket of residues in helices 3 and 5, the hinge region and the C-terminal loop. This conformational change is required for target protein binding. S100A4 might be post-translationally modified. Charged variants conceivably resulting from post-translational changes have been described in one report, but no confirmation of these findings has been forthcoming. However, calculations from the predicted isoelectric point of S100A4 and separation of the charged variants from the major spot would suggest that two variants may have displayed 17.4 and 26.1% and a third variant with a possible highly extended form and nearly 2.6-fold increase in net negative charge. Alterations in net molecular charge of this magnitude and charge distribution can alter protein configuration.
NCBI sequence: NM_002961; NP_002952; NM_019554; NP_062427; UniProtKB/Swiss-Prot: P26447.

Features
EF-hand domains:
EF hand 1: length 36; position 12-47,
EF hand 2: length 36; position 50-84.
Target protein interaction domains: in the active state S100A4 interacts with many target proteins e.g. p53 family proteins, HDM2, Annexin II, F-actin, tropomyosin, and heavy chain of non-muscle myosin IIA, among others. In a closed conformational state S100A4 is inactive, but the protein assumes an open conformation upon calcium binding. In the altered configuration S100A4 can interact with target proteins. These target proteins interact with specific binding domains of S100A4, which are accessible upon conformational change of the apoprotein upon Ca2+ binding. The Rudland/Barraclough group has shown that specific mutations that inhibit self-association of S100A4 markedly reduce its metastasis promoting effects. The mutations reduce self-association and reduce the affinity of S100A4 to two target proteins viz. p53 and non-muscle myosin heavy chain isoform A. The interaction between S100A4 and target proteins can possibly also be disrupted by the packaging of S100A4 in such a way as to sequester S100A4 dimers.
Inhibition of S100A4 polymerisation by suppressing TG2 (tissue transglutaminase 2) function has resulted in the inhibition of cell migration in vitro. This is inspired by the fact that TG2 is a cross-linking protein. Treatment of cells in vitro with EGF seems to up regulate the expression of EGFR and TG2 accompanied by enhanced cell migration. S100A4 over expressing tumours not infrequently tend to be EGFR postive; so tissue transglutaminase could be promoting EGFR dimerisation and facilitate EGF/EGFR signalling.

 
  Figure 4. S100A4 undergoes a calcium-dependent conformational rearrangement that exposes the protein target binding cleft. Ribbon diagrams showing the NMR solution structure of apo-S100A4 (PDB code 1M31) and the X-ray structure of calcium-bound S100A4 (PDB code 2Q91). Following the addition of calcium (yellow spheres), helix 3 (green helix in dark blue monomer) moves to expose the target bind cleft. This conformational rearrangement is required for S100A4 binding to protein targets. The author is grateful to Anne R. Bresnick, Ph.D., Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, for providing this illustration and the brief legend.
Expression S100A4 is distributed ubiquitously in normal tissues (Mazzucchelli, 2002).
For expression profile: Human Protein Atlas (HPA): CAB002618 and Human Protein Reference Database HPRD.
S100A4 occurs in many forms of human cancer, e.g. breast, colorectal, liver, lung, head and neck, ovarian, endometrial, pancreatic, renal, testicular, and prostate cancers, and melanoma; also in many cell lines of myeloid, lymphoid, lung and brain origin and cell lines derived from many forms of leukaemias. The expression of the gene is regulated by methylation. Over expression correlates with hypomethylation and the frequency of hypomethylation relates to tumour progression, e.g. in ovarian cancers. There is no implication at present that the degree of methylation is related to expression. S100A4 has been implicated in other human diseases, e.g. Crohn's disease and rheumatoid arthritis.
Localisation S100A4 occurs extracellulary and also in cytoplasmic and nuclear location. Differential distribution has been reported between stromal components of primary and metastatic tumour. Patterns of distribution could vary between tissues and between species. No firm functional link has been made with the site/s of localisation.
Intracellular distribution is an important factor in determining genetic activity.
It may be noted here that S100A4 is often expressed in component inflammatory cells of tumour stroma. It has been postulated that interactions between the stroma and tumour cells lead to the expression of the protein and modulate its function in either or both. However, both the postulate and its potential influence in tumour progression are yet to be established.
The pattern of intracellular distribution of many genetic determinants has been found to be highly relevant to invasion and metastasis. Nuclear location of S100A4 was shown some while ago to relate to aggressive tumour behaviour and poor prognosis. Translocation to the nucleus has been associated with EMT induced by TGF-β/Smad signalling. IL-induced translocation seems to require sumoylation of specific lysine residues and in this way conceivably regulating target gene expression. Expression patterns need to be explored in more than one tumour system. This might be crucial in the development of strategies of treatment targeting S100A4, especially with the postulated link of S100A4 expression with chemoresistance.
 
  Figure 5.
Function S100A4 protein promotes metastasis, functions as a counter point to metastasis suppressor nm23, and is implicated in the regulation of the cell cycle, cell proliferation, motility, invasion, tubulin polymerisation, and angiogenesis. S100A4 might suppress expression of other suppressor genes e.g. PRDM2 and VASH1. PRDM2 (PR domain containing 2, with ZNF domain) is a tumour suppressor gene encoding a zinc finger protein. VASH1 (vasohibin 1) inhibits cell migration, proliferation and tumour growth and angiogenesis.
S100A4 promotes metastatic spread of cancer as demonstrated by gene transfer studies. Its expression has shown clear correlation with tumour spread to lymph nodes and with prognosis.

Cell cycle, cell proliferation, tumour growth and apoptosis.
S100A4 binds to and forms complexes with p53 to regulate cell cycle progression. P53 has been confirmed as a target of S100A4, which stabilises p53. There is conclusive evidence that S100A4 binds to C-terminal regulatory region of p53. S100A4 and certain other members of the S100 family bind to TAD transactivation domain (residues 1-57) of p53. They may also affect p53 function by binding to the tetramerization domain of p53 (residues 325-355) and interfering with intracellular translocation and subcellular localisation. This interaction is suggested to be linked with p53 function. Nineteen p53 binding sites have been identified in the promoter of S100A4 (SABiosciences ChIP-qPCR Assay). S100A4 also influences p21waf1 and mdm2, a regulator of p53 function and the apoptosis family bax gene. It binds to N-terminal domain of mdm2. Signalling pathways include P53-Rb/stathmin/p53 down stream effectors, e.g. p21waf, p16 etc. P53/stathmin signalling modulates microtubule dynamics and cell division. Furthermore, p53 and down stream target apoptosis family genes such as BNIP3, caspases; calpain/Fas (?) are postulated as important pathways in S100A4 signalling. Knockdown of S100A4 has been reported to lead to apoptosis. The transcription factor NF-kappaB which involved in anti-apoptosis has been implicated in S100A4 signalling.
S100A4 proliferative signalling seems to involve epidermal growth factor receptors (EGFR). EGFR expression correlates with S100A4 expression. Interactive signalling with HER2 might be postulated with the finding that S100A4 stimulates EGFR/HER2 receptor signalling and on the identification in human S100A4 promoter of an HER2 response element 1099-1487 bp up stream of the transcription start site. The interaction of S100A4 with the TGF-beta system via Smad has also been reported. S100A4 seems able to bind to the N-ter region of Smad3. TGF-beta is an important activator of epithelial mesenchymal transition leading to acquisition of invasive ability. The interaction between S100A4 and Smad thus falls in place with the metastasis-promoting function of the former. Some of these pathways are pictorially represented above (figure 5). S100A4 activates EMT via up regulation of Snail, a negative regulator of E-cadherin. The TGF-β family receptor Activin involvement has been implicated.

Invasion, motility, and intercellular adhesion.
One of the targets of S100A4 involved in cell motility is myosin filaments. Myosin II consists of two heavy chains (MHC) with globular domains which interact with F-actin. The tail domains of heavy chains form a coiled-coil tail that participates in the assembly of myosin filaments. Wrapped round the neck region of each heavy chain are the essential and the regulatory light chains. Phosphorylation of the regulatory light chain and also of MHC plays an important part in the assesmbly of myosin II monomers into filaments. S100A4 inhibits CK2-mediated phosphorylation of MHC, inhibits the assembly of myosin monomers into filaments. The affinity of S100A4 for the myosin-IIA can be reduced by CK2-mediated phosphorylation. S100A4 destabilises MHCIIA filaments phosphorylated by PKC and inhibits the assembly of monomers. PKC and CK2 can phosphorylate distinct serine residues but yet be additive in their effect. The outcome is that S100A4 promotes dissociation of the filaments and prevents self assembly of monomers resulting in enhanced migration. Thus S100A4 seems to provide a mechanistic link between the actomyosin cytoskeletal and migration.
Signalling systems include modulation of cytoskeletal dynamics; cadherin/catenin complex cytoskeletal linkage and significantly a TCF, a component of the canonical Wnt signalling system, binding site has been identified in the S100A4 promoter and S100A4 directly binds heterodimeric beta-catenin/TCF complexes; CD44/cytoskeletal linkage; ECM associated proteolytic enzyme system/ECM remodelling, affects tubulin polymerisation. S100A4 and tumour suppressor nm23 exert opposite effects on tubulin dynamics. Two C-terminal lysine residues are required for enhanced motility and invasion and interaction with target proteins. The connective tissue growth factor (CTGF) has been reported to up regulate S100A4 expression and inhibition of S100A4 blocks CTGF-induced cell motility.
S100A4 seems to function via the MMP/TIMP system in promoting invasion as well as induction of angiogenesis. S100A4 is over expressed in invasive glioma cell lines together with down regulation of TIMP-2, indicating a close linkup of S100A4 with the MMP system in the promotion of invasion.
Angiogenesis signalling occurs via activation of MMP/TIMP; activation of angiogenic factors VEGF/endothelial cell proliferation; MetAP2/p53-mediated inhibition of endothelial cell proliferation. S100A4 stimulates angiogenic signalling in breast cancer. An indirect link is suggested by the inhibition of S100A4 by Interferon-gamma which might inhibit angiogenesis by down regulating VEGF expression. Hypoxia is a major regulator of angiogenesis. HIF-1α (hypoxia-inducible factor-1α) is a transcription regulator in hypoxia. It can activate VEGF to induce angiogenesis and TGF-α and promotes cell survival. Exposure to hypoxia has been correlated with reduced methylation of the hypoxia response element in S100A4's promoter region and enhanced HIF binding to the promoter and increased transcription of the gene together with increased cell proliferation and invasion. Given that HIF also promotes VEGF expression one can see a potential two pronged approach to control tumour growth with HIF inhibition. Some clinical studies are underway to study the effects of Sorafenib-mediated inhibition of HIF-1α and VEGF. In laboratory studies Sorafenib has been found to reduce tumour growth and tumour associated microvessel density.
Osteopontin was identified as a metastasis-associated protein some time ago. Many strands of evidence suggest that osteopontin is an intermediary in S100A4 signalling pathway. In breast cancer expression of osteopontin in the background of S100A4 has generally correlated with poor patient survival.
Osteopontin is associated with several activated NF-kappaB pathways. S100A4 induces the expression and secretion of osteopontin in some osteosarcoma cell lines in an NF-kappaB-dependent fashion. Inhibition of osteopontin inhibits tumour development and angiogenesis; inhibition of both might result in synergistic suppression of tumour progression.
Shown below are the potential pathways of S100A4 signalling in cell motility/invasion and angiogenesis, emphasising the possibility that S100A4 seems able to influence many significant systems leading to angiogenesis.

 
  Figure 6.
Homology Sequence homology to protein from Pan troglodytes (Chimpanzee) (Gene ID: 457320; Protein NCBI RefSeq: XP_001138744.1).
Bos taurus (Bovine) (Gene ID: 282343).
Canis lupus familiaris (Gene ID: 403787; NCBI reference sequence: NP_001003161.1; protein: NP_777020.1).
Sequence homology 93% to murine S100A4 (Entrez Gene ID 20198; NP_035441).
Sequence homology 91% to rat protein (Entrez Gene ID 24615; NP_036750).

Mutations

Note Many SNPs have been identified; 7 shown in NCBI and 26 in Applied Biosystems data source. The NCBI Entrez SNP database lists 19 submissions.

Chromosomal rearrangements
The locus 1q21 is a hotspot for chromosomal rearrangements, microdeletions and duplications; significance uncertain and there are no clear implications for metastasis. No translocations leading to hybrid S100A4 have been recorded.
There are 11 common and 1 rare fragile sites on chromosome 1. The common FRA1F occurs in 1q21. Chromosome 1 is prone to sister chromatid recombination (SCR) and >70% SCRs occur at the fragile sites or in the same band as the fragile sites, but no link with S100A4 established.

Germinal None reported.
Somatic No simple mutations, gene fusions, or structural variants detected in breast and colorectal carcinomas and in gliomas (Cosmic: Catalogue Of Somatic Mutations In Cancer, Welcome Trust Sanger Institute).
No mutations have been found coding regions in human, canine and feline S100A4. Mutating phenylalanine 72 to alanine reduces functional effectiveness. Toombak (tobacco rich in tobacco-specific nitrosamine) dipping (placing between the lower lip and gums) has been indirectly linked with S100A4 mutations in oral squamous cell carcinoma, but mutations have been described also in non-dippers. The carcinoma from dippers had 4 mutations (one transition, 3 transversions) and non-snuff-dippers showed 3 mutations each (one transition, 2 transversions). The suggestion is that S100A4 mutations could be complementing the effects of more frequent mutations of p53 and p21waf1.

Implicated in

Note
Entity General notes on association with human cancer
Note S100A4 has been implicated in the progression and prognosis of several forms of human cancer, e.g. breast, colorectal, gastric, pancreatic and bladder cancer, SCLC and oesophageal squamous cell carcinoma, among others. Poor prognosis associated with high S100A4 expression is accompanied by clear signs of disease progression, e.g. high histological and clinical grades and involvement of lymph nodes.
Also indicative of poor prognosis is high S100A4 expression coupled with reduced E-cadherin expression in pancreatic, oral squamous cell carcinoma and in melanoma. S100A4 expression is inversely related with expression of metastasis suppressor nm23 and with prognosis of breast cancer.
Cytogenetics No cytogenetic data are available.
Abnormal Protein No fusion proteins or hybrid genes involving S100A4 are known.
  
Entity Breast cancer
Note Both tumour and serum levels are reportedly enhanced in breast cancer patients. S100A4 expression is inversely related to that of the metastasis suppressor nm23 in breast cancers. Tumour levels might correlate with proliferative state and shown to be linked with p53 dysfunction. S100A4 proliferative signalling seems to involve epidermal growth factor receptors (EGFR). Breast cancers that are high S100A4s expressers tend to be oestrogen (ER)/progesterone receptor (PR) negative. Given that ER/PR expression is inversely related to the expression of epidermal growth factor receptors, ER/PR status together with S100A4/nm23 expression status could provide significant leads to the prediction of prognosis. S100A4 signalling could interact with HER2 function; this is suggested by the finding that S100A4 stimulates EGFR/HER2. Up regulated expression was associated with increased tumour angiogenesis and this would be expected to contribute to the invasive spread of breast cancer. Of some interest is the suggestion that phosphosulindac might target and induce apoptosis of breast cancer stem cells.
Prognosis S100A4 may be regarded as an independent predictor of prognosis.
  
Entity Colorectal cancer
Note Primary cancers show enhanced S100A4 expression and associated with metastatic disease in the lymph nodes. Up regulation of its expression has been correlated with enhanced invasion and nodal dissemination. Nuclear expression has been reported to be a prognostic indicator. As in the case of breast cancer there are indications that S100A4 might interact with and abrogate p53 function. The implied association with aggressive disease is underscored by the emergence of correlated expression of S100A4 with the extracellular matrix metalloproteinase inducer CD147/Basigin/EMMPRIN but a causal link is yet to be established. One should note in this context that S100A9 can also bind CD147.
Efforts are being made to inhibit Wnt/β-catenin mediated targeting of S100A4 using sulindac.
  
Entity Bladder cancer
Note Higher expression S100A4 has been observed and this might be associated with muscle invasion.
Prognosis High expression has been related to decreased survival.
  
Entity Oesophageal squamous cell carcinoma
Note S100A4 expression levels negatively corresponded with E-cadherin expression in ESCCs patients with metastatic disease. In vitro studies of migration of cells with experimentally enhanced S100A4 expression have lent support to the perceived relationship. Transfection of gall bladder carcinoma cell lines E-cadherin has led to the suppression of S100A4.
  
Entity Ovarian cancer
Note The expression of nuclear S100A4 expression is associated with more aggressive disease in primary carcinoma where the level of expression has been reported to be higher in solid tumours than in effusions.
  
Entity Lung cancer
Note Higher expression of S100A4 has been encountered in squamous cell but not adenocarcinoma of the lung.
Prognosis A large study of the expression levels has revealed S100A4 to be significantly predictive of survival in squamous cell but not adenocarcinoma of the lung. S100A4 was significantly associated with patients' poor prognosis in lung squamous cell carcinoma but not lung adenocarcinoma.
  
Entity Pancreatic cancer
Note S100A4 up regulation might be accompanied by reduced E-cadherin expression. This inverse relationship has also been encountered in melanoma and oral squamous cell carcinoma cell lines. This might generate an additive effect on tumour aggression.
Perineural invasion has been associated with enhanced S100A4 expression. Worthy of note is that perineural invasion is a feature linked with tumour spread and poor prognosis and its correlation with S100A4 might have implications for disease management.
Prognosis Some preliminary evidence is available indicating that S100A4 expression levels relate to shorter overall survival of patients with pancreatic cancer.
  
Entity Gastric cancer
Note Higher expression of S100A4 has been noted in gastric cancer and correlated with the presence of the tumour in lymph node and the occurrence of distant metastases, and with poor prognosis. Consistent with the situation in certain other forms of cancer, in gastric cancer S100A4 levels inversely relate to E-cadherin expression. Indeed, down regulation of E-cadherin has been found to occur in parallel with hypomethylation of S100A4.
  
Entity Melanoma
Note A marked inverse relationship has been described between S100A4 and E-cadherin in these tumours.
  
Entity Gliomas
Note S100A4 is over expressed in invasive glioma cell lines together with down regulation of TIMP-2, indicating a close linkup of S100A4 with the MMP system in the promotion of invasion. This ability to induce angiogenesis and metastatic dissemination could be complemented and indeed augmented by its postulated ability to enhance endothelial permeability. Occludin is a transmembrane tight-junction protein essential for maintaining integrity of both epithelia and endothelia. S100A4 is said to reduce occludin expression and could compromise in this way the integrity of the vascular endothelium. This might enhance endothelial permeability. Indeed the ability of tumours to form metastatic deposits in the brain has been attrributed to possible dysfunction of the blood brain barrier. If future work provides substantive evidence for this, this might have potential implication for the management of metastatic disease. But then it ought to be recognised here that gliomas do not normally metastasise to extracranial sites. Glioma cell lines do over express S100A4, but there is little information concerning the tumours. S100A8 and S100A9 have been implicated to impede diapedesis with up regulated expression of the adhesion proteins ICAM-1 and VCAM-1. S100A4 and A9 can form heterodimers in vivo and the heterodimers carry features that resemble S100A9 homodimers in respect of the ability to bind pro-inflammatory receptors. It is not known if S100A4 and A9 heterodimers and A9 homodimers differ with regard to effects on endothelial permeability.
  
Entity Crohn's disease (a form of irritable bowel disease)
Note S100A4 expression is increased in structure fibroblasts of fibrostenosing Crohn's disease promoting intestinal fibroblast migration.
  
Entity Rheumatoid arthritis
Note Increase S100A4 mRNA found in proliferating synovial fibroblasts. Also protein expression up regulated in rheumatoid arthritis synovial tissues and linked with joint invasion. IL-7 and S100A4 occurs in cartilage osteoarthritis and can lead to increased MMP-13 production by chondrocytes. The JAK/STAT/RAGE signalling has been implicated here.
  
Entity Psoriasis
Note Many S100 proteins are found in the dermis. S100A4 is up regulated in the dermis and colossal release of the protein has been reported. Enhanced stabilisation of p53 near cells expressing S100A4 has been noticed. It appears to affect cell proliferation and induce angiogenesis. Suppression of S100A4 using antibodies seems to suppress vascularisation of psoriatic skin xenografts, together with diminution of both number and size of blood vessels. There are no suggestions of co-operative or interactive function of S100A4 with S100A7 (Psoriasin).
  
Entity Cardio-vascular, nervous and pulmonary systems
Note The focus in this review is on the role of S100A4 in the disease process. Indeed, S100A4 is expressed in normal as well as in pathological conditions, subserves several physiological functions such as regulating macrophage motility, and participates in fibrosis and tissue remodeling in several diseased and damaged states, e.g. fibrosis of the kidney and loss of renal function, cardiac fibrosis, tissue repair and regeneration and wound healing; central nervous system injury, and pulmonary vascular disease.
S100A4 may be involved in disorders of these systems, but data currently available are somewhat fragmentary. Both S100A4 mRNA and protein are said to be up regulated in the hypertrophic hearts. Up regulation is associated with hypertrophy induced by aortic stenosis or myocardial infarction. In vitro, recombinant S100A4 protein increases the number of viable cardiac myocytes. The ERK1/ERK2 signalling system has been found to be activated in these processes.
Two putative neurotropic motifs have been identified in S100A4 and neuroprotective function has been attributed to the protein.
S100A4 might be associated with PAH (pulmonary arterial hypertension) and putatively linked with 17β-oestradiol modulated S100A4/RAGE signalling. A clinical trial is underway at present to study S100A4 as a marker in PAH treatment (NCT01305252).
  

Breakpoints

Note A 1q21 breakpoint was described some time ago in renal cell carcinoma (RCC)-associated (X;1)(p11;q21) translocation. This has been mapped to the S100 gene cluster, but its link with S100A4 is uncertain. No translocations involving S100A4 have been recorded. No fusion proteins or hybrid genes involving S100A4 are known.
There are 11 common and 1 rare fragile sites on chromosome 1. The common FRA1F occurs in 1q21. Chromosome 1 is prone to sister chromatid recombination (SCR) and >70% SCRs occur at the fragile sites or in the same band as the fragile sites, but no link with S100A4 has been established.

To be noted

S100A4 expression has been linked with chemoresistance, but the mechanisms involved remain to be elucidated. Whether this occurs via engagement of RAGE by S100A4 and activation of RAGE signalling leading up to chemoresistance is an avenue yet to be explored.
S100A4 activates interacting and multi-functional signalling systems, including EMT signalling systems such as Wnt/β-catenin, NF-kappaB, and E-cadherin among others, highly relevant in the context of cancer. Mediation of its function by osteopontin and potential function of S100 family proteins to act as RAGE ligands are imporatnt considerations. These would make S100A4 an eminently valuable chemotherapeutic target. Some downstream effectors of the S100A4 pathways might also lend themselves as targets of interest.
The diversity of biological effects flowing from the inappropriate expression of S100A4 and interactions of S100A4 signalling with several systems which modulate biological response would merit investigations into suppressing S100A4 expression as a possible therapeutic approach. S100A4 function is allied with growth factor and steroid hormone receptors and osteopontin which is itself subject to regulation by Wnt, NF-kappaB among others, so here is ample provision of options available for therapeutic studies. Also the perceived link up between EMT and S100A4 expression affords fresh avenues of approach.
The antihelminth drug Niclosamide which targets the Wnt/β-catenin pathway can suppress S100A4 expression with parallel inhibition of cell proliferation, migration, promotion of apoptosis, and metastatic spread in vitro and xenograft tumour models.
Xanthohumol is a prenylflavonoid antioxidant, derived from the female flowers of the hops plant (Humulus lupulus). It was identified to possess anticancer properties some while ago. Recent work has shown its ability to suppress cell proliferation, invasion and tumour progression. The flavonoid has been found to inhibit proliferation and invasion in many breast cancer cell lines, including the triple negative breast cancers MDA-MB-231 cells. It induces apoptosis and might be functioning by inhibiting Akt and NF-kappaB activation. The postulated suppression of tumour progression by Xanthohumol is based on assays purportedly resembling intravasation of tumour emboli through defects in the endothelial barrier, so needs much further scrutiny. It would be necessary to perform in vivo studies, ethically undesirable they might be, and ascertain these claims by using stringent criteria to evaluate intravasation of tumour cells and formation of metastases.
It may be noted here that Xanthohumol is said to inhibit cell motility and EMT activation and this is accompanied by inhibition of S100A4 among other determinants. Also of interest is that Xanthohumol induces apoptosis which is caspase-mediated and requires Annexin I. This might be of particular interest since S100A4 as well as other S100A proteins bind to and regulate the function of many target proteins which include annexins. Disruption of Annexin/S100A11 alters the phenotypic behaviour. Annexins display divergent effects on cell proliferation, apoptosis and invasion. The effects may relate to whether the specific S100A is a tumour promoter or suppressor. It would be needless iteration that further investigation is warranted. A clinical study of its pharmacokinetics has been undertaken (NCT01367431).
Phenanthrenes are a class of compounds originally obtained from various members of Orchidaceae and described to possess cytotoxic, antimicrobial and anti-inflammatory activity. They may be therapeutically important in preventing metastasis by inhibiting the interaction of S100A4 with its target molecules (see Bresnick AR patent WO2011146101 A1).
The induction of motility response to S100A4 seems to be mediated by Rho signalling. Rho, Rac and Cdc42 are most prominent players in cytoskeletal reorganization and modulation of cell motility. Of this RhoA has been linked with membrane ruffling and cell motility. Recently S100A4 has been shown to bind to Rhotekin, a RhoA interacting scaffold protein, via the RBD (Rho binding domain), but Rho and S1004 seem to bind to different residues of RBD. The Rho-Rhotekin-S100A4 complex generates the invasive phenotype. At the practical level it is worthy of note and future pursuit that Paclitaxel at low doses well below therapeutic levels has been shown to inhibit S100A4 in the nuclear compartment and in parallel reduce cell migration and invasion in vitro of human cholangiocarcinoma cells in a Rho-GTPase mediated manner.
Membrane bound mucins such as MUC16 (CA125) and MUC2, MUC4, MUC13 have been associated with cancer malignancy. MUC16 is associated with the formation of peritoneal metastases in ovarian cancer. MUCs 2 and 13 are over expressed in pancreatic cancer. MUC4 is overexpressed in oesophageal, lung and colon cancer. Its expression correlates with progression of pancreatic cancer. Experimental suppression of MUC4 in oesophageal cancer cells by shRNA reduces S100A4 expression and reduces cell proliferation and tumorigenic ability as compared with MUC4 expressing parent cells. The causal linkup is not established; however being integral membrane glycoproteins possibly they anchor S100A4 to the cell membrane and interferes with activation of S100A4 signalling pathways. Growth factors are known to induce phosphoryalation of the cytoplasmic domain of MUC1 and activate nuclear localization of MUC1 and β-catenin and participate in growth factor signalling.
Little is known about the involvement of the immune system in relation to S100A4 function, but there are indications that it may be recruited to NK cell immune synapses and possibly contribute to immune synapse formation. Whether S100A4 participates in restraining NK lytic function or promotes the formation and function of inhibitory synapses is uncertain. The cytoplasmic Src kinases regulate the activating or inhibitory pathways and it has been suggested S100A4 might be capable of influencing the operation of these pathways. CTLs and NK cells induce apoptosis via the pore forming protein perforin and granzyme B pathway. S100A4 may not be involved in this apoptosis pathway, but could be involved in the FasL pathway.
The non-steroidal anti-inflammatory agent sulindac has been found to interfere with Wnt signalling. The β-catenin/TCF transcription complex targets and regulates S100A4. Using an in vivo model involving intrasplenic xenografting of colon cancer cells, sulidac has been shown to down regulate S100A4 promoter activity and expression together with inhibition of Wnt/β-catenin signalling. Phosphosulindac is said to target breast CSCs in vitro and induce apoptosis.
Sulindac is currently being investigated in clinical trial on advanced stage IV colorectal cancer (NCT01856322).

Bibliography

Expression of metastasis-associated genes h-mts1 (S100A4) and nm23 in carcinoma of breast is related to disease progression.
Albertazzi E, Cajone F, Leone BE, Naguib RN, Lakshmi MS, Sherbet GV.
DNA Cell Biol. 1998b Apr;17(4):335-42.
PMID 9570150
 
The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor.
Ambartsumian N, Klingelhofer J, Grigorian M, Christensen C, Kriajevska M, Tulchinsky E, Georgiev G, Berezin V, Bock E, Rygaard J, Cao R, Cao Y, Lukanidin E.
Oncogene. 2001 Aug 2;20(34):4685-95.
PMID 11498791
 
Expression of S100A4 combined with reduced E-cadherin expression predicts patient outcome in malignant melanoma.
Andersen K, Nesland JM, Holm R, Florenes VA, Fodstad O, Maelandsmo GM.
Mod Pathol. 2004 Aug;17(8):990-7.
PMID 15133476
 
Tissue transglutaminase is an essential participant in the epidermal growth factor-stimulated signaling pathway leading to cancer cell migration and invasion.
Antonyak MA, Li B, Regan AD, Feng Q, Dusaban SS, Cerione RA.
J Biol Chem. 2009 Jul 3;284(27):17914-25. doi: 10.1074/jbc.M109.013037. Epub 2009 Apr 29.
PMID 19403524
 
Osteopontin--an important downstream effector of S100A4-mediated invasion and metastasis.
Berge G, Pettersen S, Grotterod I, Bettum IJ, Boye K, Maelandsmo GM.
Int J Cancer. 2011 Aug 15;129(4):780-90. doi: 10.1002/ijc.25735. Epub 2011 Mar 11.
PMID 20957651
 
Interferon-gamma-induced suppression of S100A4 transcription is mediated by the class II transactivator.
Boye K, Andersen K, Tveito S, Oyjord T, Maelandsmo GM.
Tumour Biol. 2007;28(1):27-35. Epub 2006 Dec 12.
PMID 17143014
 
Activation of NF-kappaB by extracellular S100A4: analysis of signal transduction mechanisms and identification of target genes.
Boye K, Grotterod I, Aasheim HC, Hovig E, Maelandsmo GM.
Int J Cancer. 2008 Sep 15;123(6):1301-10.
PMID 18548584
 
EMMPRIN is associated with S100A4 and predicts patient outcome in colorectal cancer.
Boye K, Nesland JM, Sandstad B, Haugland Haugen M, Maelandsmo GM, Flatmark K.
Br J Cancer. 2012 Aug 7;107(4):667-74. doi: 10.1038/bjc.2012.293. Epub 2012 Jul 10.
PMID 22782346
 
Preventing or inhibiting tumor metastasis in subject involves administering aromatic compound including 9,10-dihydro-phenanthrene derivative, (1,4) naphthoquinone derivative, quinoline-5,8-dione derivative, to the subject.
Bresnick AR.
US Patent WO2011146101-A1; US2013090355-A1, 2013 Apr 11.
 
The MUC4 membrane-bound mucin regulates esophageal cancer cell proliferation and migration properties: Implication for S100A4 protein.
Bruyere E, Jonckheere N, Frenois F, Mariette C, Van Seuningen I.
Biochem Biophys Res Commun. 2011 Sep 23;413(2):325-9. doi: 10.1016/j.bbrc.2011.08.095. Epub 2011 Aug 26.
PMID 21889495
 
Metastasis-associated mts1 gene expression is down-regulated by heat shock in variant cell lines of the B16 murine melanoma.
Cajone F, Debiasi S, Parker C, Lakshmi MS, Sherbet GV.
Melanoma Res. 1994 Jun;4(3):143-50.
PMID 7919958
 
Stathmin is involved in S100A4-mediated regulation of cell cycle progression.
Cajone F, Sherbet GV.
Clin Exp Metastasis. 1999;17(10):865-71.
PMID 11089885
 
Molecular cloning of the cDNA for a growth factor-inducible gene with strong homology to S-100, a calcium-binding protein.
Calabretta B, Battini R, Kaczmarek L, de Riel JK, Baserga R.
J Biol Chem. 1986 Sep 25;261(27):12628-32.
PMID 3755724
 
The metastasis promoting protein S100A4 is increased in idiopathic inflammatory myopathies.
Cerezo LA, Kuncova K, Mann H, Tomcik M, Zamecnik J, Lukanidin E, Neidhart M, Gay S, Grigorian M, Vencovsky J, Senolt L.
Rheumatology (Oxford). 2011 Oct;50(10):1766-72. doi: 10.1093/rheumatology/ker218. Epub 2011 Jun 28.
PMID 21712367
 
S100A4 silencing blocks invasive ability of esophageal squamous cell carcinoma cells.
Chen D, Zheng XF, Yang ZY, Liu DX, Zhang GY, Jiao XL, Zhao H.
World J Gastroenterol. 2012 Mar 7;18(9):915-22. doi: 10.3748/wjg.v18.i9.915.
PMID 22408350
 
Binding to intracellular targets of the metastasis-inducing protein, S100A4 (p9Ka).
Chen H, Fernig DG, Rudland PS, Sparks A, Wilkinson MC, Barraclough R.
Biochem Biophys Res Commun. 2001 Sep 7;286(5):1212-7.
PMID 11527429
 
Coupling S100A4 to Rhotekin alters Rho signaling output in breast cancer cells.
Chen M, Bresnick AR, O'Connor KL.
Oncogene. 2013 Aug 8;32(32):3754-64. doi: 10.1038/onc.2012.383. Epub 2012 Sep 10.
PMID 22964635
 
Integrin alpha6beta4 controls the expression of genes associated with cell motility, invasion, and metastasis, including S100A4/metastasin.
Chen M, Sinha M, Luxon BA, Bresnick AR, O'Connor KL.
J Biol Chem. 2009 Jan 16;284(3):1484-94. Epub 2008 Nov 14.
PMID 19011242
 
CTGF enhances the motility of breast cancer cells via an integrin-alphavbeta3-ERK1/2-dependent S100A4-upregulated pathway.
Chen PS, Wang MY, Wu SN, Su JL, Hong CC, Chuang SE, Chen MW, Hua KT, Wu YL, Cha ST, Babu MS, Chen CN, Lee PH, Chang KJ, Kuo ML.
J Cell Sci. 2007 Jun 15;120(Pt 12):2053-65.
PMID 17550972
 
Overexpression of S100A4 is closely associated with progression of colorectal cancer.
Cho YG, Kim CJ, Nam SW, Yoon SH, Lee SH, Yoo NJ, Lee JY, Park WS.
World J Gastroenterol. 2005 Aug 21;11(31):4852-6.
PMID 16097057
 
Characterization of Sp1, AP-1, CBF and KRC binding sites and minisatellite DNA as functional elements of the metastasis-associated mts1/S100A4 gene intronic enhancer.
Cohn MA, Hjelmso I, Wu LC, Guldberg P, Lukanidin EM, Tulchinsky EM.
Nucleic Acids Res. 2001 Aug 15;29(16):3335-46.
PMID 11504871
 
S100A4 expression is increased in stricture fibroblasts from patients with fibrostenosing Crohn's disease and promotes intestinal fibroblast migration.
Cunningham MF, Docherty NG, Burke JP, O'Connell PR.
Am J Physiol Gastrointest Liver Physiol. 2010 Aug;299(2):G457-66. Epub 2010 May 20.
PMID 20489045
 
Induction of the metastatic phenotype by transfection of a benign rat mammary epithelial cell line with the gene for p9Ka, a rat calcium-binding protein, but not with the oncogene EJ-ras-1.
Davies BR, Davies MP, Gibbs FE, Barraclough R, Rudland PS.
Oncogene. 1993 Apr;8(4):999-1008.
PMID 8455951
 
Expression of the rat, S-100-related, calcium-binding protein gene, p9Ka, in transgenic mice demonstrates different patterns of expression between these two species.
Davies M, Harris S, Rudland P, Barraclough R.
DNA Cell Biol. 1995 Oct;14(10):825-32.
PMID 7546288
 
Fragile sites and human disease.
Debacker K, Kooy RF.
Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R150-8. Epub 2007 Jun 13. (REVIEW)
PMID 17567780
 
Development of pulmonary arterial hypertension in mice over-expressing S100A4/Mts1 is specific to females.
Dempsie Y, Nilsen M, White K, Mair KM, Loughlin L, Ambartsumian N, Rabinovitch M, Maclean MR.
Respir Res. 2011 Dec 20;12:159. doi: 10.1186/1465-9921-12-159.
PMID 22185646
 
The metastasis-promoting S100A4 protein confers neuroprotection in brain injury.
Dmytriyeva O, Pankratova S, Owczarek S, Sonn K, Soroka V, Ridley CM, Marsolais A, Lopez-Hoyos M, Ambartsumian N, Lukanidin E, Bock E, Berezin V, Kiryushko D.
Nat Commun. 2012;3:1197. doi: 10.1038/ncomms2202.
PMID 23149742
 
S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles.
Donato R.
Int J Biochem Cell Biol. 2001 Jul;33(7):637-68. (REVIEW)
PMID 11390274
 
S100P dissociates myosin IIA filaments and focal adhesion sites to reduce cell adhesion and enhance cell migration.
Du M, Wang G, Ismail TM, Gross S, Fernig DG, Barraclough R, Rudland PS.
J Biol Chem. 2012 May 4;287(19):15330-44. doi: 10.1074/jbc.M112.349787. Epub 2012 Mar 6.
PMID 22399300
 
Regulation of myosin-IIA assembly and Mts1 binding by heavy chain phosphorylation.
Dulyaninova NG, Malashkevich VN, Almo SC, Bresnick AR.
Biochemistry. 2005 May 10;44(18):6867-76.
PMID 15865432
 
Serum metastasin mRNA is an important survival predictor in breast cancer.
El-Abd E, El-Tahan R, Fahmy L, Zaki S, Faid W, Sobhi A, Kandil K, El-Kwisky F.
Br J Biomed Sci. 2008;65(2):90-4.
PMID 19055112
 
Selective reduction in S100A4 nuclear expression by low dose paclitaxel halts invasiveness of human cholangiocarcinoma cells through a Rho-A/Cdc42 dependent mechanism.
Fabris L, Cadamuro M, Sambado L, Beretta I, Spirli C, IndraccoloS , Strazzabosco M.
J Hepatol 2012 April; 56, Suppl 2, S112.
 
Proteins of the S100 family regulate the oligomerization of p53 tumor suppressor.
Fernandez-Fernandez MR, Veprintsev DB, Fersht AR.
Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4735-40. Epub 2005 Mar 21.
PMID 15781852
 
S100A4, a mediator of metastasis.
Garrett SC, Varney KM, Weber DJ, Bresnick AR.
J Biol Chem. 2006 Jan 13;281(2):677-80. Epub 2005 Oct 21. (REVIEW)
PMID 16243835
 
Metastasis-inducing S100A4 protein: implication in non-malignant human pathologies.
Grigorian M, Ambartsumian N, Lukanidin E.
Curr Mol Med. 2008 Sep;8(6):492-6. (REVIEW)
PMID 18781956
 
Signal transduction mechanisms involved in S100A4-induced activation of the transcription factor NF-kappaB.
Grotterod I, Maelandsmo GM, Boye K.
BMC Cancer. 2010 May 28;10:241. doi: 10.1186/1471-2407-10-241.
PMID 20507646
 
The metastasis-associated protein S100A4 exists in several charged variants suggesting the presence of posttranslational modifications.
Haugen MH, Flatmark K, Mikalsen SO, Malandsmo GM.
BMC Cancer. 2008 Jun 13;8:172.
PMID 18554396
 
Metastasis-associated protein S100A4--a potential prognostic marker for colorectal cancer.
Hemandas AK, Salto-Tellez M, Maricar SH, Leong AF, Leow CK.
J Surg Oncol. 2006 May 1;93(6):498-503.
PMID 16615153
 
ERBB2 up-regulates S100A4 and several other prometastatic genes in medulloblastoma.
Hernan R, Fasheh R, Calabrese C, Frank AJ, Maclean KH, Allard D, Barraclough R, Gilbertson RJ.
Cancer Res. 2003 Jan 1;63(1):140-8.
PMID 12517790
 
S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis.
Hibino T, Sakaguchi M, Miyamoto S, Yamamoto M, Motoyama A, Hosoi J, Shimokata T, Ito T, Tsuboi R, Huh NH.
Cancer Res. 2013 Jan 1;73(1):172-83. doi: 10.1158/0008-5472.CAN-11-3843. Epub 2012 Nov 7.
PMID 23135911
 
Hypoxia upregulates ovarian cancer invasiveness via the binding of HIF-1? to a hypoxia-induced, methylation-free hypoxia response element of S100A4 gene.
Horiuchi A, Hayashi T, Kikuchi N, Hayashi A, Fuseya C, Shiozawa T, Konishi I.
Int J Cancer. 2012 Oct 15;131(8):1755-67. doi: 10.1002/ijc.27448. Epub 2012 Mar 14.
PMID 22287060
 
Short hairpin RNA-mediated inhibition of S100A4 promotes apoptosis and suppresses proliferation of BGC823 gastric cancer cells in vitro and in vivo.
Hua J, Chen D, Fu H, Zhang R, Shen W, Liu S, Sun K, Sun X.
Cancer Lett. 2010 Jun 1;292(1):41-7. doi: 10.1016/j.canlet.2009.11.007. Epub 2009 Nov 28.
PMID 19945782
 
Mutations of the cell cycle arrest gene p21WAF1, but not the metastasis-inducing gene S100A4, are frequent in oral squamous cell carcinomas from Sudanese toombak dippers and non-snuff-dippers from the Sudan, Scandinavia, USA and UK.
Ibrahim SO, Lillehaug JR, Dolphine O, Johnson NW, Warnakulasuriya KA, Vasstrand EN.
Anticancer Res. 2002 May-Jun;22(3):1445-51.
PMID 12168821
 
S100A4 mRNA is a diagnostic and prognostic marker in pancreatic carcinoma.
Ikenaga N, Ohuchida K, Mizumoto K, Yu J, Fujita H, Nakata K, Ueda J, Sato N, Nagai E, Tanaka M.
J Gastrointest Surg. 2009 Oct;13(10):1852-8. Epub 2009 Aug 4.
PMID 19653048
 
S100A4 expression with reduced E-cadherin expression predicts distant metastasis of human malignant melanoma cell lines in the NOD/SCID/gammaCnull (NOG) mouse model.
Ikoma N, Yamazaki H, Abe Y, Oida Y, Ohnishi Y, Suemizu H, Matsumoto H, Matsuyama T, Ohta Y, Ozawa A, Ueyama Y, Nakamura M.
Oncol Rep. 2005 Sep;14(3):633-7.
PMID 16077966
 
The basic C-terminal amino acids of calcium-binding protein S100A4 promote metastasis.
Ismail TM, Fernig DG, Rudland PS, Terry CJ, Wang G, Barraclough R.
Carcinogenesis. 2008 Dec;29(12):2259-66. Epub 2008 Sep 10.
PMID 18784356
 
Self-association of calcium-binding protein S100A4 and metastasis.
Ismail TM, Zhang S, Fernig DG, Gross S, Martin-Fernandez ML, See V, Tozawa K, Tynan CJ, Wang G, Wilkinson MC, Rudland PS, Barraclough R.
J Biol Chem. 2010 Jan 8;285(2):914-22. Epub 2009 Nov 16.
PMID 19917604
 
A growth-related mRNA in cultured mouse cells encodes a placental calcium binding protein.
Jackson-Grusby LL, Swiergiel J, Linzer DI.
Nucleic Acids Res. 1987 Aug 25;15(16):6677-90.
PMID 3628004
 
Activation of Smad-mediated TGF-? signaling triggers epithelial-mesenchymal transitions in murine cloned corneal progenitor cells.
Kawakita T, Espana EM, Higa K, Kato N, Li W, Tseng SC.
J Cell Physiol. 2013 Jan;228(1):225-34. doi: 10.1002/jcp.24126.
PMID 22674610
 
Nuclear expression of S100A4 is associated with aggressive behavior of epithelial ovarian carcinoma: an important autocrine/paracrine factor in tumor progression.
Kikuchi N, Horiuchi A, Osada R, Imai T, Wang C, Chen X, Konishi I.
Cancer Sci. 2006 Oct;97(10):1061-9.
PMID 16984379
 
Enhanced S100A4 protein expression is clinicopathologically significant to metastatic potential and p53 dysfunction in colorectal cancer.
Kim JH, Kim CN, Kim SY, Lee JS, Cho D, Kim JW, Yoon SY.
Oncol Rep. 2009 Jul;22(1):41-7.
PMID 19513503
 
Epidermal growth factor receptor ligands as new extracellular targets for the metastasis-promoting S100A4 protein.
Klingelhofer J, Moller HD, Sumer EU, Berg CH, Poulsen M, Kiryushko D, Soroka V, Ambartsumian N, Grigorian M, Lukanidin EM.
FEBS J. 2009 Oct;276(20):5936-48. Epub 2009 Sep 9.
PMID 19740107
 
Metastasis-associated protein Mts1 (S100A4) inhibits CK2-mediated phosphorylation and self-assembly of the heavy chain of nonmuscle myosin.
Kriajevska M, Bronstein IB, Scott DJ, Tarabykina S, Fischer-Larsen M, Issinger O, Lukanidin E.
Biochim Biophys Acta. 2000 Dec 20;1498(2-3):252-63.
PMID 11108967
 
Metastasis associated MTS1 and NM23 genes affect tubulin polymerisation in B16 melanomas: a possible mechanism of their regulation of metastatic behaviour of tumours.
Lakshmi MS, Parker C, Sherbet GV.
Anticancer Res. 1993 Mar-Apr;13(2):299-303.
PMID 8390799
 
Expression of S100A4 and Met: potential predictors for metastasis and survival in early-stage breast cancer.
Lee WY, Su WC, Lin PW, Guo HR, Chang TW, Chen HH.
Oncology. 2004;66(6):429-38.
PMID 15452371
 
The unique cytoplasmic domain of human Fc?RIIIA regulates receptor-mediated function.
Li X, Baskin JG, Mangan EK, Su K, Gibson AW, Ji C, Edberg JC, Kimberly RP.
J Immunol. 2012 Nov 1;189(9):4284-94. doi: 10.4049/jimmunol.1200704. Epub 2012 Sep 28.
PMID 23024279
 
Frequent S100A4 Expression with Unique Splicing Pattern in Gastric Cancers: A Hypomethylation Event Paralleled with E-cadherin Reduction and Wnt Activation.
Li Y, Zhang KL, Sun Y, Yang Y, Chen XY, Kong QY, Wu ML, Liu J, Li H.
Transl Oncol. 2008 Dec;1(4):165-76.
PMID 19043527
 
S100A4 regulates macrophage chemotaxis.
Li ZH, Dulyaninova NG, House RP, Almo SC, Bresnick AR.
Mol Biol Cell. 2010 Aug 1;21(15):2598-610. doi: 10.1091/mbc.E09-07-0609. Epub 2010 Jun 2.
PMID 20519440
 
Mts1 regulates the assembly of nonmuscle myosin-IIA.
Li ZH, Spektor A, Varlamova O, Bresnick AR.
Biochemistry. 2003 Dec 9;42(48):14258-66.
PMID 14640694
 
Sorafenib inhibits hypoxia-inducible factor-1? synthesis: implications for antiangiogenic activity in hepatocellular carcinoma.
Liu LP, Ho RL, Chen GG, Lai PB.
Clin Cancer Res. 2012 Oct 15;18(20):5662-71. doi: 10.1158/1078-0432.CCR-12-0552. Epub 2012 Aug 28.
PMID 22929805
 
Human S100A4 (p9Ka) induces the metastatic phenotype upon benign tumour cells.
Lloyd BH, Platt-Higgins A, Rudland PS, Barraclough R.
Oncogene. 1998 Jul 30;17(4):465-73.
PMID 9696040
 
Niclosamide suppresses cancer cell growth by inducing Wnt co-receptor LRP6 degradation and inhibiting the Wnt/b-catenin pathway.
Lu W, Lin C, Roberts MJ, Waud WR, Piazza GA, Li Y.
PLoS One. 2011;6(12):e29290. doi: 10.1371/journal.pone.0029290. Epub 2011 Dec 16.
PMID 22195040
 
Multiple distinct NK-cell synapses.
Mace EM, Orange JS.
Blood. 2011 Dec 15;118(25):6475-6. doi: 10.1182/blood-2011-10-381392.
PMID 22174302
 
Different expression and clinical role of S100A4 in serous ovarian carcinoma at different anatomic sites.
Maelandsmo GM, Florenes VA, Nguyen MT, Flatmark K, Davidson B.
Tumour Biol. 2009;30(1):15-25. Epub 2009 Feb 5.
PMID 19194111
 
S100A4 contributes to the suppression of BNIP3 expression, chemoresistance, and inhibition of apoptosis in pancreatic cancer.
Mahon PC, Baril P, Bhakta V, Chelala C, Caulee K, Harada T, Lemoine NR.
Cancer Res. 2007 Jul 15;67(14):6786-95.
PMID 17638890
 
Phenothiazines inhibit S100A4 function by inducing protein oligomerization.
Malashkevich VN, Dulyaninova NG, Ramagopal UA, Liriano MA, Varney KM, Knight D, Brenowitz M, Weber DJ, Almo SC, Bresnick AR.
Proc Natl Acad Sci U S A. 2010 May 11;107(19):8605-10. doi: 10.1073/pnas.0913660107. Epub 2010 Apr 26.
PMID 20421509
 
Genetic analysis of the epidermal differentiation complex (EDC) on human chromosome 1q21: chromosomal orientation, new markers, and a 6-Mb YAC contig.
Marenholz I, Volz A, Ziegler A, Davies A, Ragoussis I, Korge BP, Mischke D.
Genomics. 1996 Nov 1;37(3):295-302.
PMID 8938441
 
Transglutaminase down-regulates the dimerization of epidermal growth factor receptor in rat perivenous and periportal hepatocytes.
Maruko A, Ohtake Y, Katoh S, Ohkubo Y.
Cell Prolif. 2009 Oct;42(5):647-56. doi: 10.1111/j.1365-2184.2009.00622.x. Epub 2009 Jul 9.
PMID 19614676
 
Expression of S100A2 and S100A4 predicts for disease progression and patient survival in bladder cancer.
Matsumoto K, Irie A, Satoh T, Ishii J, Iwabuchi K, Iwamura M, Egawa S, Baba S.
Urology. 2007 Sep;70(3):602-7. Epub 2007 Aug 3.
PMID 17688917
 
Functional interaction between Smad3 and S100A4 (metastatin-1) for TGF-beta-mediated cancer cell invasiveness.
Matsuura I, Lai CY, Chiang KN.
Biochem J. 2010 Feb 24;426(3):327-35.
PMID 20070253
 
Absence of S100A4 (mts1) gene mutations in various canine and feline tumours. Detection of a polymorphism in feline S100A4 (mts1).
Mayr B, Brem G, Reifinger M.
J Vet Med A Physiol Pathol Clin Med. 2000 Mar;47(2):123-8.
PMID 10803111
 
Protein S100A4: too long overlooked by pathologists?
Mazzucchelli L.
Am J Pathol. 2002 Jan;160(1):7-13.
PMID 11786392
 
Overexpression of S100A4 in human cancer cell lines resistant to methotrexate.
Mencia N, Selga E, Rico I, de Almagro MC, Villalobos X, Ramirez S, Adan J, Hernandez JL, Noe V, Ciudad CJ.
BMC Cancer. 2010 Jun 1;10:250.
PMID 20515499
 
Overexpression of the 18A2/mts1 gene and down-regulation of the TIMP-2 gene in invasive human glioma cell lines in vitro.
Merzak A, Parker C, Koochekpour S, Sherbet GV, Pilkington GJ.
Neuropathol Appl Neurobiol. 1994 Dec;20(6):614-9.
PMID 7898625
 
Sumoylation and nuclear translocation of S100A4 regulate IL-1beta-mediated production of matrix metalloproteinase-13.
Miranda KJ, Loeser RF, Yammani RR.
J Biol Chem. 2010 Oct 8;285(41):31517-24. doi: 10.1074/jbc.M110.125898. Epub 2010 Aug 4.
PMID 20685652
 
Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex ("epidermal differentiation complex") on human chromosome 1q21.
Mischke D, Korge BP, Marenholz I, Volz A, Ziegler A.
J Invest Dermatol. 1996 May;106(5):989-92.
PMID 8618063
 
MUC4 (mucin 4, cell surface associated)
Moniaux N, Chaturvedi P, Van Seuningen I, Porchet N, Singh AP, Batra SK.
Atlas Genet Cytogenet Oncol Haematol. 2007; 11(3):201-206. URL: http://AtlasGeneticsOncology.org/Genes/MUC4ID41459ch3q29.html
 
S100A4 regulates E-cadherin expression in oral squamous cell carcinoma.
Moriyama-Kita M, Endo Y, Yonemura Y, Heizmann CW, Miyamori H, Sato H, Yamamoto E, Sasaki T.
Cancer Lett. 2005 Dec 18;230(2):211-8.
PMID 16297707
 
Increased expression of S100A4 and its prognostic significance in esophageal squamous cell carcinoma.
Ninomiya I, Ohta T, Fushida S, Endo Y, Hashimoto T, Yagi M, Fujimura T, Nishimura G, Tani T, Shimizu K, Yonemura Y, Heizmann CW, Schafer BW, Sasaki T, Miwa K.
Int J Oncol. 2001 Apr;18(4):715-20.
PMID 11251165
 
Potential role for S100A4 in the disruption of the blood-brain barrier in collagen-induced arthritic mice, an animal model of rheumatoid arthritis.
Nishioku T, Furusho K, Tomita A, Ohishi H, Dohgu S, Shuto H, Yamauchi A, Kataoka Y.
Neuroscience. 2011 Aug 25;189:286-92. doi: 10.1016/j.neuroscience.2011.05.044. Epub 2011 May 26.
PMID 21627981
 
Activin type IB receptor signaling in prostate cancer cells promotes lymph node metastasis in a xenograft model.
Nomura M, Tanaka K, Wang L, Goto Y, Mukasa C, Ashida K, Takayanagi R.
Biochem Biophys Res Commun. 2013 Jan 4;430(1):340-6. doi: 10.1016/j.bbrc.2012.11.011. Epub 2012 Nov 15.
PMID 23159635
 
The role of osteopontin in tumorigenesis and metastasis.
Oates AJ, Barraclough R, Rudland PS.
Invasion Metastasis. 1997;17(1):1-15. (REVIEW)
PMID 9425320
 
Increased S100A4 expression combined with decreased E-cadherin expression predicts a poor outcome of patients with pancreatic cancer.
Oida Y, Yamazaki H, Tobita K, Mukai M, Ohtani Y, Miyazaki N, Abe Y, Imaizumi T, Makuuchi H, Ueyama Y, Nakamura M.
Oncol Rep. 2006 Sep;16(3):457-63.
PMID 16865243
 
Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations.
Osada T, Chen M, Yang XY, Spasojevic I, Vandeusen JB, Hsu D, Clary BM, Clay TM, Chen W, Morse MA, Lyerly HK.
Cancer Res. 2011 Jun 15;71(12):4172-82. doi: 10.1158/0008-5472.CAN-10-3978. Epub 2011 Apr 29.
PMID 21531761
 
The metastasis associated protein S100A4: a potential novel link to inflammation and consequent aggressive behaviour of rheumatoid arthritis synovial fibroblasts.
Oslejskova L, Grigorian M, Gay S, Neidhart M, Senolt L.
Ann Rheum Dis. 2008 Nov;67(11):1499-504. Epub 2007 Dec 4. (REVIEW)
PMID 18056757
 
Induction of 18A2/mts1 gene expression and its effects on metastasis and cell cycle control.
Parker C, Whittaker PA, Usmani BA, Lakshmi MS, Sherbet GV.
DNA Cell Biol. 1994 Oct;13(10):1021-8.
PMID 7945934
 
An integrated genomic analysis of human glioblastoma multiforme.
Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW.
Science. 2008 Sep 26;321(5897):1807-12. Epub 2008 Sep 4.
PMID 18772396
 
Crystal structure of metastasis-associated protein S100A4 in the active calcium-bound form.
Pathuri P, Vogeley L, Luecke H.
J Mol Biol. 2008 Oct 31;383(1):62-77. doi: 10.1016/j.jmb.2008.04.076. Epub 2008 May 7.
PMID 18783790
 
S100 proteins: a missing piece in the puzzle of heart failure?
Pleger ST, Most P, Katus HA.
Cardiovasc Res. 2007 Jul 1;75(1):1-2. Epub 2007 May 10.
PMID 17531210
 
MUC1 oncoprotein functions in activation of fibroblast growth factor receptor signaling.
Ren J, Raina D, Chen W, Li G, Huang L, Kufe D.
Mol Cancer Res. 2006 Nov;4(11):873-83.
PMID 17114345
 
Prognostic significance of the metastasis-inducing protein S100A4 (p9Ka) in human breast cancer.
Rudland PS, Platt-Higgins A, Renshaw C, West CR, Winstanley JH, Robertson L, Barraclough R.
Cancer Res. 2000 Mar 15;60(6):1595-603.
PMID 10749128
 
Novel effect of antihelminthic Niclosamide on S100A4-mediated metastatic progression in colon cancer.
Sack U, Walther W, Scudiero D, Selby M, Kobelt D, Lemm M, Fichtner I, Schlag PM, Shoemaker RH, Stein U.
J Natl Cancer Inst. 2011 Jul 6;103(13):1018-36. doi: 10.1093/jnci/djr190. Epub 2011 Jun 17.
PMID 21685359
 
Isolation of a YAC clone covering a cluster of nine S100 genes on human chromosome 1q21: rationale for a new nomenclature of the S100 calcium-binding protein family.
Schafer BW, Wicki R, Engelkamp D, Mattei MG, Heizmann CW.
Genomics. 1995 Feb 10;25(3):638-43.
PMID 7759097
 
Proteome analysis of distinct developmental stages of human natural killer (NK) cells.
Scheiter M, Lau U, van Ham M, Bulitta B, Grobe L, Garritsen H, Klawonn F, Konig S, Jansch L.
Mol Cell Proteomics. 2013 May;12(5):1099-114. doi: 10.1074/mcp.M112.024596. Epub 2013 Jan 13.
PMID 23315794
 
Functional significance of metastasis-inducing S100A4(Mts1) in tumor-stroma interplay.
Schmidt-Hansen B, Klingelhofer J, Grum-Schwensen B, Christensen A, Andresen S, Kruse C, Hansen T, Ambartsumian N, Lukanidin E, Grigorian M.
J Biol Chem. 2004 Jun 4;279(23):24498-504. Epub 2004 Mar 26.
PMID 15047714
 
S100A4: a common mediator of epithelial-mesenchymal transition, fibrosis and regeneration in diseases?
Schneider M, Hansen JL, Sheikh SP.
J Mol Med (Berl). 2008 May;86(5):507-22. doi: 10.1007/s00109-007-0301-3. Epub 2008 Mar 6. (REVIEW)
PMID 18322670
 
The modus operandi of S100A4 signalling in cancer growth, progression and prognosis.
Sherbet GV, Lakshmi MS.
The molecular and cellular pathology of cancer progression and prognosis. Sherbet GV (ed.), 2006; pp. 359-377.
 
Therapeutic strategies in cancer biology and pathology.
Sherbet GV.
E-book 2013 Aug; Elsevier.
 
The consensus coding sequences of human breast and colorectal cancers.
Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE.
Science. 2006 Oct 13;314(5797):268-74. Epub 2006 Sep 7.
PMID 16959974
 
Intervening in beta-catenin signaling by sulindac inhibits S100A4-dependent colon cancer metastasis.
Stein U, Arlt F, Smith J, Sack U, Herrmann P, Walther W, Lemm M, Fichtner I, Shoemaker RH, Schlag PM.
Neoplasia. 2011 Feb;13(2):131-44.
PMID 21403839
 
Binding of pEL98 protein, an S100-related calcium-binding protein, to nonmuscle tropomyosin.
Takenaga K, Nakamura Y, Sakiyama S, Hasegawa Y, Sato K, Endo H.
J Cell Biol. 1994 Mar;124(5):757-68.
PMID 8120097
 
Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts.
Tamaki Y, Iwanaga Y, Niizuma S, Kawashima T, Kato T, Inuzuka Y, Horie T, Morooka H, Takase T, Akahashi Y, Kobuke K, Ono K, Shioi T, Sheikh SP, Ambartsumian N, Lukanidin E, Koshimizu TA, Miyazaki S, Kimura T.
J Mol Cell Cardiol. 2013 Apr;57:72-81. doi: 10.1016/j.yjmcc.2013.01.007. Epub 2013 Jan 23.
PMID 23352991
 
The expression of S100A4 in human pancreatic cancer is associated with invasion.
Tsukamoto N, Egawa S, Akada M, Abe K, Saiki Y, Kaneko N, Yokoyama S, Shima K, Yamamura A, Motoi F, Abe H, Hayashi H, Ishida K, Moriya T, Tabata T, Kondo E, Kanai N, Gu Z, Sunamura M, Unno M, Horii A.
Pancreas. 2013 Aug;42(6):1027-33. doi: 10.1097/MPA.0b013e31828804e7.
PMID 23851436
 
Significance of S100A4 as a prognostic marker of lung squamous cell carcinoma.
Tsuna M, Kageyama S, Fukuoka J, Kitano H, Doki Y, Tezuka H, Yasuda H.
Anticancer Res. 2009 Jul;29(7):2547-54.
PMID 19596927
 
A kappaB-related binding site is an integral part of the mts1 gene composite enhancer element located in the first intron of the gene.
Tulchinsky E, Prokhortchouk E, Georgiev G, Lukanidin E.
J Biol Chem. 1997 Feb 21;272(8):4828-35.
PMID 9030539
 
Electric charge balance mechanism of extended soluble proteins.
Uchikoga N, Takahashi SY, Ke R, Sonoyama M, Mitaku S.
Protein Sci. 2005 Jan;14(1):74-80. Epub 2004 Dec 2.
PMID 15576568
 
Solution structure of human Mts1 (S100A4) as determined by NMR spectroscopy.
Vallely KM, Rustandi RR, Ellis KC, Varlamova O, Bresnick AR, Weber DJ.
Biochemistry. 2002 Oct 22;41(42):12670-80.
PMID 12379109
 
Myeloid-related proteins 8 and 14 induce a specific inflammatory response in human microvascular endothelial cells.
Viemann D, Strey A, Janning A, Jurk K, Klimmek K, Vogl T, Hirono K, Ichida F, Foell D, Kehrel B, Gerke V, Sorg C, Roth J.
Blood. 2005 Apr 1;105(7):2955-62. Epub 2004 Dec 14.
PMID 15598812
 
Xanthohumol attenuates tumour cell-mediated breaching of the lymphendothelial barrier and prevents intravasation and metastasis.
Viola K, Kopf S, Rarova L, Jarukamjorn K, Kretschy N, Teichmann M, Vonach C, Atanasov AG, Giessrigl B, Huttary N, Raab I, Krieger S, Strnad M, de Martin R, Saiko P, Szekeres T, Knasmuller S, Dirsch VM, Jager W, Grusch M, Dolznig H, Mikulits W, Krupitza G.
Arch Toxicol. 2013 Jul;87(7):1301-12. doi: 10.1007/s00204-013-1028-2. Epub 2013 Mar 17.
PMID 23503627
 
Expression status of S100A14 and S100A4 correlates with metastatic potential and clinical outcome in colorectal cancer after surgery.
Wang HY, Zhang JY, Cui JT, Tan XH, Li WM, Gu J, Lu YY.
Oncol Rep. 2010 Jan;23(1):45-52.
PMID 19956863
 
High-level expression of S100A4 correlates with lymph node metastasis and poor prognosis in patients with gastric cancer.
Wang YY, Ye ZY, Zhao ZS, Tao HQ, Chu YQ.
Ann Surg Oncol. 2010 Jan;17(1):89-97. Epub 2009 Oct 10.
PMID 19820999
 
The role of TG2 in regulating S100A4-mediated mammary tumour cell migration.
Wang Z, Griffin M.
PLoS One. 2013;8(3):e57017. doi: 10.1371/journal.pone.0057017. Epub 2013 Mar 1.
PMID 23469180
 
Calvasculin, as a factor affecting the microfilament assemblies in rat fibroblasts transfected by src gene.
Watanabe Y, Usada N, Minami H, Morita T, Tsugane S, Ishikawa R, Kohama K, Tomida Y, Hidaka H.
FEBS Lett. 1993 Jun 7;324(1):51-5.
PMID 8504859
 
Interleukin-7 stimulates secretion of S100A4 by activating the JAK/STAT signaling pathway in human articular chondrocytes.
Yammani RR, Long D, Loeser RF.
Arthritis Rheum. 2009 Mar;60(3):792-800.
PMID 19248116
 
Elevation of S100A4 expression in buccal mucosal fibroblasts by arecoline: involvement in the pathogenesis of oral submucous fibrosis.
Yu CC, Tsai CH, Hsu HI, Chang YC.
PLoS One. 2013;8(1):e55122. doi: 10.1371/journal.pone.0055122. Epub 2013 Jan 31.
PMID 23383075
 
A mechanism for the upregulation of EGF receptor levels in glioblastomas.
Zhang J, Antonyak MA, Singh G, Cerione RA.
Cell Rep. 2013 Jun 27;3(6):2008-20. doi: 10.1016/j.celrep.2013.05.021. Epub 2013 Jun 13.
PMID 23770238
 
The C-terminal region of S100A4 is important for its metastasis-inducing properties.
Zhang S, Wang G, Liu D, Bao Z, Fernig DG, Rudland PS, Barraclough R.
Oncogene. 2005 Jun 23;24(27):4401-11.
PMID 15856021
 
Metastasin leads to poor prognosis of hepatocellular carcinoma through partly inducing EMT.
Zheng X, Gai X, Wu Z, Liu Q, Yao Y.
Oncol Rep. 2013 May;29(5):1811-8. doi: 10.3892/or.2013.2341. Epub 2013 Mar 12.
PMID 23483190
 
Phosphosulindac (OXT-328) selectively targets breast cancer stem cells in vitro and in human breast cancer xenografts.
Zhu C, Cheng KW, Ouyang N, Huang L, Sun Y, Constantinides P, Rigas B.
Stem Cells. 2012 Oct;30(10):2065-75. doi: 10.1002/stem.1139.
PMID 22653497
 
Significance of the S100A4 protein in psoriasis.
Zibert JR, Skov L, Thyssen JP, Jacobsen GK, Grigorian M.
J Invest Dermatol. 2010 Jan;130(1):150-60.
PMID 19641515
 
Association of S100A4 and osteopontin with specific prognostic factors and survival of patients with minimally invasive breast cancer.
de Silva Rudland S, Martin L, Roshanlall C, Winstanley J, Leinster S, Platt-Higgins A, Carroll J, West C, Barraclough R, Rudland P.
Clin Cancer Res. 2006 Feb 15;12(4):1192-200.
PMID 16489073
 
S100 proteins interact with the N-terminal domain of MDM2.
van Dieck J, Lum JK, Teufel DP, Fersht AR.
FEBS Lett. 2010 Aug 4;584(15):3269-74. Epub 2010 Jun 19.
PMID 20591429
 

Citation

This paper should be referenced as such :
Sherbet, GV
S100A4 (S100 Calcium Binding Protein A4)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(6):381-396.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/S100A4ID42192ch1q21.html
History of this paper:
Sherbet, GV. S100A4 (S100 calcium binding protein A4). Atlas Genet Cytogenet Oncol Haematol. 2011;15(10):877-886.
http://documents.irevues.inist.fr/bitstream/handle/2042/46036/03-2011-S100A4ID42192ch1q21.pdf


External links

Nomenclature
HGNC (Hugo)S100A4   10494
Cards
AtlasS100A4ID42192ch1q21
Entrez_Gene (NCBI)S100A4  6275  S100 calcium binding protein A4
Aliases18A2; 42A; CAPL; FSP1; 
MTS1; P9KA; PEL98
GeneCards (Weizmann)S100A4
Ensembl hg19 (Hinxton)ENSG00000196154 [Gene_View]  chr1:153516098-153518282 [Contig_View]  S100A4 [Vega]
Ensembl hg38 (Hinxton)ENSG00000196154 [Gene_View]  chr1:153516098-153518282 [Contig_View]  S100A4 [Vega]
ICGC DataPortalENSG00000196154
TCGA cBioPortalS100A4
AceView (NCBI)S100A4
Genatlas (Paris)S100A4
WikiGenes6275
SOURCE (Princeton)S100A4
Genetics Home Reference (NIH)S100A4
Genomic and cartography
GoldenPath hg19 (UCSC)S100A4  -     chr1:153516098-153518282 -  1q12-q22   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)S100A4  -     1q12-q22   [Description]    (hg38-Dec_2013)
EnsemblS100A4 - 1q12-q22 [CytoView hg19]  S100A4 - 1q12-q22 [CytoView hg38]
Mapping of homologs : NCBIS100A4 [Mapview hg19]  S100A4 [Mapview hg38]
OMIM114210   
Gene and transcription
Genbank (Entrez)AK292083 AV735911 AY762982 BC000838 BC016300
RefSeq transcript (Entrez)NM_002961 NM_019554
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)S100A4
Cluster EST : UnigeneHs.654444 [ NCBI ]
CGAP (NCI)Hs.654444
Alternative Splicing GalleryENSG00000196154
Gene ExpressionS100A4 [ NCBI-GEO ]   S100A4 [ EBI - ARRAY_EXPRESS ]   S100A4 [ SEEK ]   S100A4 [ MEM ]
Gene Expression Viewer (FireBrowse)S100A4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6275
GTEX Portal (Tissue expression)S100A4
Protein : pattern, domain, 3D structure
UniProt/SwissProtP26447   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP26447  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP26447
Splice isoforms : SwissVarP26447
PhosPhoSitePlusP26447
Domaine pattern : Prosite (Expaxy)EF_HAND_1 (PS00018)    EF_HAND_2 (PS50222)    S100_CABP (PS00303)   
Domains : Interpro (EBI)EF-hand-dom_pair    EF_Hand_1_Ca_BS    EF_hand_dom    S100/CaBP-9k_CS    S100_Ca-bd_sub   
Domain families : Pfam (Sanger)S_100 (PF01023)   
Domain families : Pfam (NCBI)pfam01023   
Domain families : Smart (EMBL)EFh (SM00054)  S_100 (SM01394)  
Conserved Domain (NCBI)S100A4
DMDM Disease mutations6275
Blocks (Seattle)S100A4
PDB (SRS)1M31    2LNK    2MRD    2Q91    3C1V    3CGA    3KO0    3M0W    3ZWH    4CFQ    4CFR    4ETO    4HSZ   
PDB (PDBSum)1M31    2LNK    2MRD    2Q91    3C1V    3CGA    3KO0    3M0W    3ZWH    4CFQ    4CFR    4ETO    4HSZ   
PDB (IMB)1M31    2LNK    2MRD    2Q91    3C1V    3CGA    3KO0    3M0W    3ZWH    4CFQ    4CFR    4ETO    4HSZ   
PDB (RSDB)1M31    2LNK    2MRD    2Q91    3C1V    3CGA    3KO0    3M0W    3ZWH    4CFQ    4CFR    4ETO    4HSZ   
Structural Biology KnowledgeBase1M31    2LNK    2MRD    2Q91    3C1V    3CGA    3KO0    3M0W    3ZWH    4CFQ    4CFR    4ETO    4HSZ   
SCOP (Structural Classification of Proteins)1M31    2LNK    2MRD    2Q91    3C1V    3CGA    3KO0    3M0W    3ZWH    4CFQ    4CFR    4ETO    4HSZ   
CATH (Classification of proteins structures)1M31    2LNK    2MRD    2Q91    3C1V    3CGA    3KO0    3M0W    3ZWH    4CFQ    4CFR    4ETO    4HSZ   
SuperfamilyP26447
Human Protein AtlasENSG00000196154
Peptide AtlasP26447
HPRD15914
IPIIPI00032313   IPI01012346   
Protein Interaction databases
DIP (DOE-UCLA)P26447
IntAct (EBI)P26447
FunCoupENSG00000196154
BioGRIDS100A4
STRING (EMBL)S100A4
ZODIACS100A4
Ontologies - Pathways
QuickGOP26447
Ontology : AmiGOepithelial to mesenchymal transition  actin binding  calcium ion binding  protein binding  extracellular space  nucleus  identical protein binding  neuron projection  positive regulation of I-kappaB kinase/NF-kappaB signaling  poly(A) RNA binding  calcium-dependent protein binding  perinuclear region of cytoplasm  RAGE receptor binding  extracellular exosome  
Ontology : EGO-EBIepithelial to mesenchymal transition  actin binding  calcium ion binding  protein binding  extracellular space  nucleus  identical protein binding  neuron projection  positive regulation of I-kappaB kinase/NF-kappaB signaling  poly(A) RNA binding  calcium-dependent protein binding  perinuclear region of cytoplasm  RAGE receptor binding  extracellular exosome  
NDEx NetworkS100A4
Atlas of Cancer Signalling NetworkS100A4
Wikipedia pathwaysS100A4
Orthology - Evolution
OrthoDB6275
GeneTree (enSembl)ENSG00000196154
Phylogenetic Trees/Animal Genes : TreeFamS100A4
HOVERGENP26447
HOGENOMP26447
Homologs : HomoloGeneS100A4
Homology/Alignments : Family Browser (UCSC)S100A4
Gene fusions - Rearrangements
Fusion : MitelmanGTF2F2/S100A4 [13q14.12/1q21.3]  [t(1;13)(q21;q14)]  
Fusion: TCGAGTF2F2 13q14.12 S100A4 1q21.3 BLCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerS100A4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)S100A4
dbVarS100A4
ClinVarS100A4
1000_GenomesS100A4 
Exome Variant ServerS100A4
ExAC (Exome Aggregation Consortium)S100A4 (select the gene name)
Genetic variants : HAPMAP6275
Genomic Variants (DGV)S100A4 [DGVbeta]
DECIPHER (Syndromes)1:153516098-153518282  ENSG00000196154
CONAN: Copy Number AnalysisS100A4 
Mutations
ICGC Data PortalS100A4 
TCGA Data PortalS100A4 
Broad Tumor PortalS100A4
OASIS PortalS100A4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICS100A4  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDS100A4
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch S100A4
DgiDB (Drug Gene Interaction Database)S100A4
DoCM (Curated mutations)S100A4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)S100A4 (select a term)
intoGenS100A4
NCG5 (London)S100A4
Cancer3DS100A4(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM114210   
Orphanet
MedgenS100A4
Genetic Testing Registry S100A4
NextProtP26447 [Medical]
TSGene6275
GENETestsS100A4
Huge Navigator S100A4 [HugePedia]
snp3D : Map Gene to Disease6275
BioCentury BCIQS100A4
ClinGenS100A4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD6275
Chemical/Pharm GKB GenePA34906
Clinical trialS100A4
Miscellaneous
canSAR (ICR)S100A4 (select the gene name)
Probes
Litterature
PubMed270 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineS100A4
EVEXS100A4
GoPubMedS100A4
iHOPS100A4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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