Atlas of Genetics and Cytogenetics in Oncology and Haematology
TNS4 (tensin 4) Saleh Al-Ghamdi, Mohammad Ilyas
King Abdullah International Medical Research Center, National Guard Health Affairs, Riyadh 11426, Saudi Arabia; Division of Pathology, Nottingham University, Nottingham, UK (SAG), Nottingham Digestive Diseases Centre, NIHR Biomedical Research Unit, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK; Division of Pathology, Nottingham University, Nottingham, UK (MI)
Published in Atlas Database: April 2012
Online updated version : http://AtlasGeneticsOncology.org/Genes/TNS4ID40190ch17q21.html DOI: 10.4267/2042/48143
Note The TNS4 gene was identified by Lo and Lo. They found that it is composed of 12 exons encoding an mRNA of 4015 bp with an open reading frame encoding 715 amino acid residues. The amino acids 418-715 are very similar to the COOH termini of tensin 1, tensin 2 and tensin 3. There are six potential tyrosine phosphorylation sites found in TNS4 although the gene product is a shorter polypeptide and lacks the NH2-terminal homologous regions found in tensins. This gene was found to be distant member of the tensin family and given name cten for the COOH-terminal tensin-like molecule.
DNA/RNA Note It was found that the human cten gene is located on chromosome 17q12-21 and has 12 exons. The SH2 domains bind ligands containing pTyr residues within a specific sequence and high affinity binding is provided by the pTyr residue itself and by subsequent residues toward the COOH-terminal.
Protein Note TNS4, as the others tensins, contains a phosphotyrosine-binding domain (PTB), which plays the role of interacting with the cytoplasmic tail of the β-integrin. Also they all contain, at the C-terminal, Src homology domain 2 (SH2 domain).
Figure 1. Analysis of cten amino acid sequence. A. The cDNA-derived amino acid sequence of human cten. The potential tyrosine phosphorylation sites are in bold. B. Organization of human cten gene. Exon/intron boundaries were determined by comparison of sequences of genomic DNA and cDNA. In the splice site, exon sequences are indicated by uppercase letters, and intron sequences are indicated by lowercase letters. Codon phase refers to the codon split at the splice acceptor. Introns that do not split codon triplets are indicated by phase 0, interruption after the first nucleotide is indicated by codon phase I, and interruption after the second nucleotide is indicated by codon phase II. N indicates noncoding region. Numbers in the brackets indicate the sizes of the corresponding exons in human tensin 1 and tensin 2, respectively.
Figure 2. Schematic structure of tensins. The C-terminus of tensin contains SH2 and PTB domains, allowing TNS4 to interact with tyrosine-phosphorylated proteins and β integrin respectively. The FAB domain is present in the C-terminal region, and it involved in mediating binding of tensin 4 to other focal adhesion molecules.
While tensin 1, tensin 2 and tensin 3 interact with actin at multiple sites in the N-terminal, tensin 4 (Cten) lacks the n-terminal region actin binding domain (ABD). TNS4 has only one focal adhesion binding (FAB) domains in C- terminal while others have it in both N- and C-terminals.
Expression The expression of Cten messenger RNA (mRNA) was evaluated in normal tissues by K. Sakashita et al. using the human total RNA master panel and found that Cten is expressed at high levels in prostate, oesophagus,
breast and salivary glands. Moderate Cten expression was found in the thyroid and trachea. In contrast, very low expression was reported in colon, lung, small intestine, spleen, kidney, stomach and testis.
Localisation It is localized to focal adhesions.
Function The TNS4 is having a role in the cell motility by enhancing the migration as well as the invasion too. Also TNS4 is found to play a central role in HGF-
induced tubulogenesis. The role of TNS4 on cell proliferation is found to be minimal and not up to the level of the effect of migration. By enhancing the motility and having the effect on the tubulogenesis, TNS4 is believed to have a role in cancer cell metastasis.
Mutations Note No mutation has been reported.
Implicated in Various cancers Note The role of cten in cancer is not well defined. In prostate cancer it is down-regulated, where in normal cells it is localized to focal adhesions recruiting the tumour suppressor, deleted in liver cancer (DLC-1), thus suppressing tumorigenesis. Cten in prostate epithelial cells has also been found to regulate staurosporine-induced apoptosis where cten is cleaved by caspase 3 and results in reduction in cell growth rate. Therefore, loss of cten expression may lead to uncontrolled cell growth and result in cell transformation. Accordingly, in prostate cancer, cten may function as a tumour suppressor protein. On the other hand, cten has been found to be up-regulated in a number of cancers. It is up-regulated in lung cancer and correlates with tumour progression. In breast cancer, the epidermal growth factor receptor (EGFR), which is involved in various cellular processes including proliferation and motility, up-regulates cten and down-regulates tensin 3. Tensin 3 is localized in cell matrix adhesions but it disappears upon EGF stimulation. These findings showed that EGF-induced up-regulation of cten and down-regulation of tensin 3 correlates with cten fibre remodelling. Cten disassembles actin stress fibres through its PTB domain which competes with tensin 3 for the cytoplasmic tail of integrins displacing it from focal adhesion sites. Indeed, cten in breast cancer is a potential marker of a poorly differentiated relatively aggressive sub-population of invasive breast tumours. In colorectal cancer (CRC) and pancreatic cancer, cten has also been found to be up-regulated and is localized to both cytoplasm and nucleus. It is regulated by Kras signalling (and probably EGFR upstream of Kras) and possibly by Stat3 signalling.
References Lo SH, Lo TB. Cten, a COOH-terminal tensin-like protein with prostate restricted expression, is down-regulated in prostate cancer. Cancer Res. 2002 Aug 1;62(15):4217-21
Sasaki H, Moriyama S, Mizuno K, Yukiue H, Konishi A, Yano M, Kaji M, Fukai I, Kiriyama M, Yamakawa Y, Fujii Y. Cten mRNA expression was correlated with tumor progression in lung cancers. Lung Cancer. 2003 May;40(2):151-5
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Lo SS, Lo SH, Lo SH. Cleavage of cten by caspase-3 during apoptosis. Oncogene. 2005 Jun 16;24(26):4311-4
Katz M, Amit I, Citri A, Shay T, Carvalho S, Lavi S, Milanezi F, Lyass L, Amariglio N, Jacob-Hirsch J, Ben-Chetrit N, Tarcic G, Lindzen M, Avraham R, Liao YC, Trusk P, Lyass A, Rechavi G, Spector NL, Lo SH, Schmitt F, Bacus SS, Yarden Y. A reciprocal tensin-3-cten switch mediates EGF-driven mammary cell migration. Nat Cell Biol. 2007 Aug;9(8):961-9
Liao YC, Si L, deVere White RW, Lo SH. The phosphotyrosine-independent interaction of DLC-1 and the SH2 domain of cten regulates focal adhesion localization and growth suppression activity of DLC-1. J Cell Biol. 2007 Jan 1;176(1):43-9
Sakashita K, Mimori K, Tanaka F, Kamohara Y, Inoue H, Sawada T, Hirakawa K, Mori M. Prognostic relevance of Tensin4 expression in human gastric cancer. Ann Surg Oncol. 2008 Sep;15(9):2606-13
Albasri A, Seth R, Jackson D, Benhasouna A, Crook S, Nateri AS, Chapman R, Ilyas M. C-terminal Tensin-like (CTEN) is an oncogene which alters cell motility possibly through repression of E-cadherin in colorectal cancer. J Pathol. 2009 May;218(1):57-65
Chan LK, Ko FC, Ng IO, Yam JW. Deleted in liver cancer 1 (DLC1) utilizes a novel binding site for Tensin2 PTB domain interaction and is required for tumor-suppressive function. PLoS One. 2009;4(5):e5572
Liao YC, Chen NT, Shih YP, Dong Y, Lo SH. Up-regulation of C-terminal tensin-like molecule promotes the tumorigenicity of colon cancer through beta-catenin. Cancer Res. 2009 Jun 1;69(11):4563-6
Barbieri I, Pensa S, Pannellini T, Quaglino E, Maritano D, Demaria M, Voster A, Turkson J, Cavallo F, Watson CJ, Provero P, Musiani P, Poli V. Constitutively active Stat3 enhances neu-mediated migration and metastasis in mammary tumors via upregulation of Cten. Cancer Res. 2010 Mar 15;70(6):2558-67
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Albasri A, Aleskandarany M, Benhasouna A, Powe DG, Ellis IO, Ilyas M, Green AR. CTEN (C-terminal tensin-like), a novel oncogene overexpressed in invasive breast carcinoma of poor prognosis. Breast Cancer Res Treat. 2011 Feb;126(1):47-54
Albasri A, Al-Ghamdi S, Fadhil W, Aleskandarany M, Liao YC, Jackson D, Lobo DN, Lo SH, Kumari R, Durrant L, Watson S, Kindle KB, Ilyas M. Cten signals through integrin-linked kinase (ILK) and may promote metastasis in colorectal cancer. Oncogene. 2011 Jun 30;30(26):2997-3002
Al-Ghamdi S, Albasri A, Cachat J, Ibrahem S, Muhammad BA, Jackson D, Nateri AS, Kindle KB, Ilyas M. Cten is targeted by Kras signalling to regulate cell motility in the colon and pancreas. PLoS One. 2011;6(6):e20919
Kwon SH, Nedvetsky PI, Mostov KE. Transcriptional profiling identifies TNS4 function in epithelial tubulogenesis. Curr Biol. 2011 Jan 25;21(2):161-6
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