TNS4 (tensin 4)

2012-04-01 Saleh Al-Ghamdi , Mohammad Ilyas Affiliation

Identity

HGNC

TNS4

LOCATION

17q21.2

LOCUSID

84951

ALIAS

CTEN,PP14434

FUSION GENES

Show Gene Fusions

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.

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.

Proteins

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). 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.

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.

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

Entity name

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.

Bibliography

Pubmed ID	Last Year	Title	Authors
21698197	2011	Cten is targeted by Kras signalling to regulate cell motility in the colon and pancreas.	Al-Ghamdi S et al
21339732	2011	Cten signals through integrin-linked kinase (ILK) and may promote metastasis in colorectal cancer.	Albasri A et al
19214987	2009	C-terminal Tensin-like (CTEN) is an oncogene which alters cell motility possibly through repression of E-cadherin in colorectal cancer.	Albasri A et al
20215508	2010	Constitutively active Stat3 enhances neu-mediated migration and metastasis in mammary tumors via upregulation of Cten.	Barbieri I et al
19440389	2009	Deleted in liver cancer 1 (DLC1) utilizes a novel binding site for Tensin2 PTB domain interaction and is required for tumor-suppressive function.	Chan LK et al
17643115	2007	A reciprocal tensin-3-cten switch mediates EGF-driven mammary cell migration.	Katz M et al
21236678	2011	Transcriptional profiling identifies TNS4 function in epithelial tubulogenesis.	Kwon SH et al
19725034	2010	CTEN/tensin 4 expression induces sensitivity to paclitaxel in prostate cancer.	Li Y et al
19487278	2009	Up-regulation of C-terminal tensin-like molecule promotes the tumorigenicity of colon cancer through beta-catenin.	Liao YC et al
17190795	2007	The phosphotyrosine-independent interaction of DLC-1 and the SH2 domain of cten regulates focal adhesion localization and growth suppression activity of DLC-1.	Liao YC et al
12154022	2002	Cten, a COOH-terminal tensin-like protein with prostate restricted expression, is down-regulated in prostate cancer.	Lo SH et al
15806167	2005	Cleavage of cten by caspase-3 during apoptosis.	Lo SS et al
18612693	2008	Prognostic relevance of Tensin4 expression in human gastric cancer.	Sakashita K et al
12711115	2003	Cten mRNA expression was correlated with tumor progression in lung cancers.	Sasaki H et al
15001839	2003	Cten mRNA expression is correlated with tumor progression in thymoma.	Sasaki H et al

Other Information

Locus ID:

NCBI: 84951
MIM: 608385
HGNC: 24352
Ensembl: ENSG00000131746

Variants:

dbSNP: 84951
ClinVar: 84951
TCGA: ENSG00000131746
COSMIC: TNS4

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000131746	ENST00000254051	Q8IZW8
ENSG00000131746	ENST00000582747	J3QLA4

Expression (GTEx)

100

150

200

250

300

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Signal Transduction	REACTOME	R-HSA-162582
Signaling by MET	REACTOME	R-HSA-6806834
MET promotes cell motility	REACTOME	R-HSA-8875878
MET interacts with TNS proteins	REACTOME	R-HSA-8875513

References

Pubmed ID	Year	Title	Citations
19913121	2009	Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.	85
17643115	2007	A reciprocal tensin-3-cten switch mediates EGF-driven mammary cell migration.	68
17190795	2007	The phosphotyrosine-independent interaction of DLC-1 and the SH2 domain of cten regulates focal adhesion localization and growth suppression activity of DLC-1.	66
19487278	2009	Up-regulation of C-terminal tensin-like molecule promotes the tumorigenicity of colon cancer through beta-catenin.	25
19194507	2009	Tensin3 is a negative regulator of cell migration and all four Tensin family members are downregulated in human kidney cancer.	22
12711115	2003	Cten mRNA expression was correlated with tumor progression in lung cancers.	20
21339732	2011	Cten signals through integrin-linked kinase (ILK) and may promote metastasis in colorectal cancer.	20
20390342	2011	CTEN (C-terminal tensin-like), a novel oncogene overexpressed in invasive breast carcinoma of poor prognosis.	18
21698197	2011	Cten is targeted by Kras signalling to regulate cell motility in the colon and pancreas.	17
24814316	2014	Tensin-4-dependent MET stabilization is essential for survival and proliferation in carcinoma cells.	16

Citation

Saleh Al-Ghamdi ; Mohammad Ilyas

TNS4 (tensin 4)

Atlas Genet Cytogenet Oncol Haematol. 2012-04-01

Online version: http://atlasgeneticsoncology.org/gene/40190/tns4