S100A4 (S100 Calcium Binding Protein A4)

2013-11-01   Gajanan V Sherbet 

School of Electrical, Electronic, Computer Engineering, University of Newcastle upon Tyne, UK, Institute for Molecular Medicine, Huntington Beach, CA, USA

Identity

HGNC
LOCATION
1q21.3
IMAGE
Atlas Image
LEGEND
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).
LOCUSID
ALIAS
18A2,42A,CAPL,FSP1,MTS1,P9KA,PEL98
FUSION GENES

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.
Atlas Image
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.

Proteins

Atlas Image
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.

Atlas Image
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. Crohns 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.
Atlas Image
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 S100A4s 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.

Atlas Image
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

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

Entity name
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.
Fusion protein
No fusion proteins or hybrid genes involving S100A4 are known.
Entity name
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 name
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 name
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 name
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 name
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 name
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 name
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 name
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 name
Melanoma
Note
A marked inverse relationship has been described between S100A4 and E-cadherin in these tumours.
Entity name
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 name
Crohns disease (a form of irritable bowel disease)
Note
S100A4 expression is increased in structure fibroblasts of fibrostenosing Crohns disease promoting intestinal fibroblast migration.
Entity name
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 name
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 name
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).

Bibliography

Pubmed IDLast YearTitleAuthors
95701501998Expression of metastasis-associated genes h-mts1 (S100A4) and nm23 in carcinoma of breast is related to disease progression.Albertazzi E et al
114987912001The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor.Ambartsumian N et al
151334762004Expression of S100A4 combined with reduced E-cadherin expression predicts patient outcome in malignant melanoma.Andersen K et al
194035242009Tissue transglutaminase is an essential participant in the epidermal growth factor-stimulated signaling pathway leading to cancer cell migration and invasion.Antonyak MA et al
209576512011Osteopontin--an important downstream effector of S100A4-mediated invasion and metastasis.Berge G et al
171430142007Interferon-gamma-induced suppression of S100A4 transcription is mediated by the class II transactivator.Boye K et al
185485842008Activation of NF-kappaB by extracellular S100A4: analysis of signal transduction mechanisms and identification of target genes.Boye K et al
227823462012EMMPRIN is associated with S100A4 and predicts patient outcome in colorectal cancer.Boye K et al
218894952011The MUC4 membrane-bound mucin regulates esophageal cancer cell proliferation and migration properties: Implication for S100A4 protein.Bruyère E et al
79199581994Metastasis-associated mts1 gene expression is down-regulated by heat shock in variant cell lines of the B16 murine melanoma.Cajone F et al
110898851999Stathmin is involved in S100A4-mediated regulation of cell cycle progression.Cajone F et al
37557241986Molecular cloning of the cDNA for a growth factor-inducible gene with strong homology to S-100, a calcium-binding protein.Calabretta B et al
217123672011The metastasis promoting protein S100A4 is increased in idiopathic inflammatory myopathies.Cerezo LA et al
224083502012S100A4 silencing blocks invasive ability of esophageal squamous cell carcinoma cells.Chen D et al
115274292001Binding to intracellular targets of the metastasis-inducing protein, S100A4 (p9Ka).Chen H et al
229646352013Coupling S100A4 to Rhotekin alters Rho signaling output in breast cancer cells.Chen M et al
190112422009Integrin alpha6beta4 controls the expression of genes associated with cell motility, invasion, and metastasis, including S100A4/metastasin.Chen M et al
175509722007CTGF enhances the motility of breast cancer cells via an integrin-alphavbeta3-ERK1/2-dependent S100A4-upregulated pathway.Chen PS et al
160970572005Overexpression of S100A4 is closely associated with progression of colorectal cancer.Cho YG et al
115048712001Characterization 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 et al
204890452010S100A4 expression is increased in stricture fibroblasts from patients with fibrostenosing Crohn's disease and promotes intestinal fibroblast migration.Cunningham MF et al
84559511993Induction 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 et al
75462881995Expression 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 et al
175677802007Fragile sites and human disease.Debacker K et al
221856462011Development of pulmonary arterial hypertension in mice over-expressing S100A4/Mts1 is specific to females.Dempsie Y et al
231497422012The metastasis-promoting S100A4 protein confers neuroprotection in brain injury.Dmytriyeva O et al
113902742001S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles.Donato R et al
223993002012S100P dissociates myosin IIA filaments and focal adhesion sites to reduce cell adhesion and enhance cell migration.Du M et al
158654322005Regulation of myosin-IIA assembly and Mts1 binding by heavy chain phosphorylation.Dulyaninova NG et al
190551122008Serum metastasin mRNA is an important survival predictor in breast cancer.El-Abd E et al
157818522005Proteins of the S100 family regulate the oligomerization of p53 tumor suppressor.Fernandez-Fernandez MR et al
162438352006S100A4, a mediator of metastasis.Garrett SC et al
187819562008Metastasis-inducing S100A4 protein: implication in non-malignant human pathologies.Grigorian M et al
205076462010Signal transduction mechanisms involved in S100A4-induced activation of the transcription factor NF-kappaB.Grotterød I et al
185543962008The metastasis-associated protein S100A4 exists in several charged variants suggesting the presence of posttranslational modifications.Haugen MH et al
166151532006Metastasis-associated protein S100A4--a potential prognostic marker for colorectal cancer.Hemandas AK et al
125177902003ERBB2 up-regulates S100A4 and several other prometastatic genes in medulloblastoma.Hernan R et al
231359112013S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis.Hibino T et al
222870602012Hypoxia upregulates ovarian cancer invasiveness via the binding of HIF-1α to a hypoxia-induced, methylation-free hypoxia response element of S100A4 gene.Horiuchi A et al
199457822010Short hairpin RNA-mediated inhibition of S100A4 promotes apoptosis and suppresses proliferation of BGC823 gastric cancer cells in vitro and in vivo.Hua J et al
121688212002Mutations 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 et al
196530482009S100A4 mRNA is a diagnostic and prognostic marker in pancreatic carcinoma.Ikenaga N et al
160779662005S100A4 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 et al
187843562008The basic C-terminal amino acids of calcium-binding protein S100A4 promote metastasis.Ismail TM et al
199176042010Self-association of calcium-binding protein S100A4 and metastasis.Ismail TM et al
36280041987A growth-related mRNA in cultured mouse cells encodes a placental calcium binding protein.Jackson-Grusby LL et al
226746102013Activation of Smad-mediated TGF-β signaling triggers epithelial-mesenchymal transitions in murine cloned corneal progenitor cells.Kawakita T et al
169843792006Nuclear expression of S100A4 is associated with aggressive behavior of epithelial ovarian carcinoma: an important autocrine/paracrine factor in tumor progression.Kikuchi N et al
195135032009Enhanced S100A4 protein expression is clinicopathologically significant to metastatic potential and p53 dysfunction in colorectal cancer.Kim JH et al
197401072009Epidermal growth factor receptor ligands as new extracellular targets for the metastasis-promoting S100A4 protein.Klingelhöfer J et al
111089672000Metastasis-associated protein Mts1 (S100A4) inhibits CK2-mediated phosphorylation and self-assembly of the heavy chain of nonmuscle myosin.Kriajevska M et al
83907991993Metastasis associated MTS1 and NM23 genes affect tubulin polymerisation in B16 melanomas: a possible mechanism of their regulation of metastatic behaviour of tumours.Lakshmi MS et al
154523712004Expression of S100A4 and Met: potential predictors for metastasis and survival in early-stage breast cancer.Lee WY et al
230242792012The unique cytoplasmic domain of human FcγRIIIA regulates receptor-mediated function.Li X et al
190435272008Frequent S100A4 Expression with Unique Splicing Pattern in Gastric Cancers: A Hypomethylation Event Paralleled with E-cadherin Reduction and Wnt Activation.Li Y et al
205194402010S100A4 regulates macrophage chemotaxis.Li ZH et al
146406942003Mts1 regulates the assembly of nonmuscle myosin-IIA.Li ZH et al
229298052012Sorafenib inhibits hypoxia-inducible factor-1α synthesis: implications for antiangiogenic activity in hepatocellular carcinoma.Liu LP et al
96960401998Human S100A4 (p9Ka) induces the metastatic phenotype upon benign tumour cells.Lloyd BH et al
221950402011Niclosamide suppresses cancer cell growth by inducing Wnt co-receptor LRP6 degradation and inhibiting the Wnt/β-catenin pathway.Lu W et al
221743022011Multiple distinct NK-cell synapses.Mace EM et al
191941112009Different expression and clinical role of S100A4 in serous ovarian carcinoma at different anatomic sites.Maelandsmo GM et al
176388902007S100A4 contributes to the suppression of BNIP3 expression, chemoresistance, and inhibition of apoptosis in pancreatic cancer.Mahon PC et al
204215092010Phenothiazines inhibit S100A4 function by inducing protein oligomerization.Malashkevich VN et al
89384411996Genetic analysis of the epidermal differentiation complex (EDC) on human chromosome 1q21: chromosomal orientation, new markers, and a 6-Mb YAC contig.Marenholz I et al
196146762009Transglutaminase down-regulates the dimerization of epidermal growth factor receptor in rat perivenous and periportal hepatocytes.Maruko A et al
176889172007Expression of S100A2 and S100A4 predicts for disease progression and patient survival in bladder cancer.Matsumoto K et al
200702532010Functional interaction between Smad3 and S100A4 (metastatin-1) for TGF-beta-mediated cancer cell invasiveness.Matsuura I et al
108031112000Absence of S100A4 (mts1) gene mutations in various canine and feline tumours. Detection of a polymorphism in feline S100A4 (mts1).Mayr B et al
117863922002Protein S100A4: too long overlooked by pathologists?Mazzucchelli L et al
205154992010Overexpression of S100A4 in human cancer cell lines resistant to methotrexate.Mencía N et al
78986251994Overexpression of the 18A2/mts1 gene and down-regulation of the TIMP-2 gene in invasive human glioma cell lines in vitro.Merzak A et al
206856522010Sumoylation and nuclear translocation of S100A4 regulate IL-1beta-mediated production of matrix metalloproteinase-13.Miranda KJ et al
86180631996Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex ("epidermal differentiation complex") on human chromosome 1q21.Mischke D et al
162977072005S100A4 regulates E-cadherin expression in oral squamous cell carcinoma.Moriyama-Kita M et al
112511652001Increased expression of S100A4 and its prognostic significance in esophageal squamous cell carcinoma.Ninomiya I et al
216279812011Potential role for S100A4 in the disruption of the blood-brain barrier in collagen-induced arthritic mice, an animal model of rheumatoid arthritis.Nishioku T et al
231596352013Activin type IB receptor signaling in prostate cancer cells promotes lymph node metastasis in a xenograft model.Nomura M et al
94253201997The role of osteopontin in tumorigenesis and metastasis.Oates AJ et al
168652432006Increased S100A4 expression combined with decreased E-cadherin expression predicts a poor outcome of patients with pancreatic cancer.Oida Y et al
215317612011Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations.Osada T et al
180567572008The metastasis associated protein S100A4: a potential novel link to inflammation and consequent aggressive behaviour of rheumatoid arthritis synovial fibroblasts.Oslejsková L et al
79459341994Induction of 18A2/mts1 gene expression and its effects on metastasis and cell cycle control.Parker C et al
187723962008An integrated genomic analysis of human glioblastoma multiforme.Parsons DW et al
187837902008Crystal structure of metastasis-associated protein S100A4 in the active calcium-bound form.Pathuri P et al
175312102007S100 proteins: a missing piece in the puzzle of heart failure?Pleger ST et al
171143452006MUC1 oncoprotein functions in activation of fibroblast growth factor receptor signaling.Ren J et al
107491282000Prognostic significance of the metastasis-inducing protein S100A4 (p9Ka) in human breast cancer.Rudland PS et al
216853592011Novel effect of antihelminthic Niclosamide on S100A4-mediated metastatic progression in colon cancer.Sack U et al
77590971995Isolation 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.Schäfer BW et al
233157942013Proteome analysis of distinct developmental stages of human natural killer (NK) cells.Scheiter M et al
150477142004Functional significance of metastasis-inducing S100A4(Mts1) in tumor-stroma interplay.Schmidt-Hansen B et al
183226702008S100A4: a common mediator of epithelial-mesenchymal transition, fibrosis and regeneration in diseases?Schneider M et al
169599742006The consensus coding sequences of human breast and colorectal cancers.Sjöblom T et al
214038392011Intervening in β-catenin signaling by sulindac inhibits S100A4-dependent colon cancer metastasis.Stein U et al
81200971994Binding of pEL98 protein, an S100-related calcium-binding protein, to nonmuscle tropomyosin.Takenaga K et al
233529912013Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts.Tamaki Y et al
238514362013The expression of S100A4 in human pancreatic cancer is associated with invasion.Tsukamoto N et al
195969272009Significance of S100A4 as a prognostic marker of lung squamous cell carcinoma.Tsuna M et al
90305391997A 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 et al
155765682005Electric charge balance mechanism of extended soluble proteins.Uchikoga N et al
123791092002Solution structure of human Mts1 (S100A4) as determined by NMR spectroscopy.Vallely KM et al
155988122005Myeloid-related proteins 8 and 14 induce a specific inflammatory response in human microvascular endothelial cells.Viemann D et al
235036272013Xanthohumol attenuates tumour cell-mediated breaching of the lymphendothelial barrier and prevents intravasation and metastasis.Viola K et al
199568632010Expression status of S100A14 and S100A4 correlates with metastatic potential and clinical outcome in colorectal cancer after surgery.Wang HY et al
198209992010High-level expression of S100A4 correlates with lymph node metastasis and poor prognosis in patients with gastric cancer.Wang YY et al
234691802013The role of TG2 in regulating S100A4-mediated mammary tumour cell migration.Wang Z et al
85048591993Calvasculin, as a factor affecting the microfilament assemblies in rat fibroblasts transfected by src gene.Watanabe Y et al
192481162009Interleukin-7 stimulates secretion of S100A4 by activating the JAK/STAT signaling pathway in human articular chondrocytes.Yammani RR et al
233830752013Elevation of S100A4 expression in buccal mucosal fibroblasts by arecoline: involvement in the pathogenesis of oral submucous fibrosis.Yu CC et al
237702382013A mechanism for the upregulation of EGF receptor levels in glioblastomas.Zhang J et al
158560212005The C-terminal region of S100A4 is important for its metastasis-inducing properties.Zhang S et al
234831902013Metastasin leads to poor prognosis of hepatocellular carcinoma through partly inducing EMT.Zheng X et al
226534972012Phosphosulindac (OXT-328) selectively targets breast cancer stem cells in vitro and in human breast cancer xenografts.Zhu C et al
196415152010Significance of the S100A4 protein in psoriasis.Zibert JR et al
164890732006Association of S100A4 and osteopontin with specific prognostic factors and survival of patients with minimally invasive breast cancer.de Silva Rudland S et al
205914292010S100 proteins interact with the N-terminal domain of MDM2.van Dieck J et al

Other Information

Locus ID:

NCBI: 6275
MIM: 114210
HGNC: 10494
Ensembl: ENSG00000196154

Variants:

dbSNP: 6275
ClinVar: 6275
TCGA: ENSG00000196154
COSMIC: S100A4

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000196154ENST00000354332P26447
ENSG00000196154ENST00000368714P26447
ENSG00000196154ENST00000368715P26447
ENSG00000196154ENST00000368716P26447

Expression (GTEx)

0
500
1000
1500

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
200191882010S100A4 and metastasis: a small actor playing many roles.148
162438352006S100A4, a mediator of metastasis.112
157884162005Metastasis-associated protein S100A4 induces angiogenesis through interaction with Annexin II and accelerated plasmin formation.79
169904292006S100A4 accelerates tumorigenesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9.75
169481162006Increase in production of matrix metalloproteinase 13 by human articular chondrocytes due to stimulation with S100A4: Role of the receptor for advanced glycation end products.68
233160182013Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: role of the S100A4-miR155-SOCS1-MMP9 axis.68
190112422009Integrin alpha6beta4 controls the expression of genes associated with cell motility, invasion, and metastasis, including S100A4/metastasin.62
196158022009Epithelial-mesenchymal transition as a potential explanation for podocyte depletion in diabetic nephropathy.57
242401142014Neutrophils promote the malignant glioma phenotype through S100A4.55
157818522005Proteins of the S100 family regulate the oligomerization of p53 tumor suppressor.53

Citation

Gajanan V Sherbet

S100A4 (S100 Calcium Binding Protein A4)

Atlas Genet Cytogenet Oncol Haematol. 2013-11-01

Online version: http://atlasgeneticsoncology.org/gene/42192/s100a4id42192ch1q21

Historical Card

2011-03-01 S100A4 (S100 Calcium Binding Protein A4) by  Gajanan V Sherbet 

School of Electrical, Electronic, Computer Engineering, University of Newcastle upon Tyne, UK, Institute for Molecular Medicine, Huntington Beach, CA, USA