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Tensins are focal adhesion proteins that regulate various biological processes, such as mechanical sensing, cell adhesion, migration, invasion, and proliferation, through their multiple binding activities that transduce critical signals across the plasma membrane. When these molecular interactions and/or mediated signaling are disrupted, cellular activities and tissue functions are compromised, leading to disease development. Here, we focus on the significance of the tensin family in renal function and diseases. The expression pattern of each tensin in the kidney, their roles in chronic kidney diseases, renal cell carcinoma, and their potentials as prognostic markers and/or therapeutic targets are discussed in this review. [ABSTRACT FROM AUTHOR]

Tensin is a focal adhesion molecule that is known to regulate cell adhesion, migration, and proliferation. Although there are four tensin homologs (TNS1, TNS2, TNS3, and CTEN/TNS4) in mammals, only one tensin gene is found in Caenorhabditis elegans. Sequence analysis suggests that Caenorhabditis elegans tensin is slightly closer aligned with human TNS1 than with other human tensins. To establish the role of TNS1 in Caenorhabditis elegans , we have generated TNS1 knockout (KO) worms by CRISPR-Cas9 and homologous recombination directed repair approaches. Lack of TNS1 does not appear to affect the development or gross morphology of the worms. Nonetheless, defecation cycles are significantly longer in TNS1 KO worms. In addition, their pharyngeal pumping rate is markedly faster, which is likely due to a shorter pump duration in the KO worms. These findings indicate that TNS1 is not required for the development and survival of Caenorhabditis elegans but point to a critical role in modulating defecation and pharyngeal pumping rates. • Although four tensin members are found in mammals, C elegans only has one tensin (TNS1) gene. • TNS1 is not required for the development and survival of C elegans. • Lack of TNS1 significantly extend defecation cycles in worms. • The pharyngeal pumping rates in TNS1 knockout worm are markedly faster. • TNS1 regulates pharyngeal pumping rates in C elegans. [ABSTRACT FROM AUTHOR]

Abstract: C-terminal tensin-like (cten, also known as tensin4, TNS4) is a member of the tensin family. Cten protein, like the other three tensin family members, localizes to focal adhesion sites but only shares sequence homology with other tensins at its C-terminal region, which contains the SH2 and PTB domains. Cten is abundantly expressed in normal prostate and placenta and is down-regulated in prostate cancer. However, overexpression of cten frequently associates with tumors derived from breast, colon, lung, stomach, skin and pancreas. A variety of cancer-associated growth factors and cytokines induce cten expression. Up-regulated cten promotes cell motility, prolongs epidermal growth factor receptor signaling, and enhances tumorigenicity. Emerging findings suggest that cten is a promising biomarker and therapeutic target for various cancers. [Copyright &y& Elsevier]

Abstract: Deleted in liver cancer 1 (DLC-1), as its name implied, was originally isolated as a potential tumor suppressor gene often deleted in hepatocellular carcinoma. Further studies have indicated that down-expression of DLC-1 either by genomic deletion or DNA methylation is associated with a variety of cancer types including lung, breast, prostate, kidney, colon, uterus, ovary, and stomach. Re-expression of DLC-1 in cancer cells regulates the structure of actin cytoskeleton and focal adhesions and significantly inhibits cell growth, supporting its role as a tumor suppressor. This tumor suppressive function relies on DLC-1''s RhoGTPase activating protein (RhoGAP) activity and steroidogenic acute regulatory (StAR)-related lipid transfer (START) domain, as well as its focal adhesion localization, which is recruited by the Src Homology 2 (SH2) domains of tensins in a phosphotyrosine-independent fashion. Therefore, the expression and subcellular localization of DLC-1 could be a useful molecular marker for cancer prognosis, whereas DLC-1 and its downstream signaling molecules might be therapeutic targets for the treatment of cancer. [Copyright &y& Elsevier]

Abstract: The cytoplasmic side of focal adhesions is comprised of large molecular complexes that link transmembrane receptors, such as integrins, to the actin cytoskeleton and mediate signals modulating cell attachment, migration, proliferation, differentiation, and gene expression. These complexes are heterogeneous and dynamic structures that are apparent targets of regulatory signals that control the function of focal adhesions. Recent studies using genetic approaches in invertebrate and vertebrate systems have begun to reveal the structure and function of these complexes in vivo. [Copyright &y& Elsevier]

Abstract: Using a talin2 gene-trapped embryonic stem cell clone, we have developed a talin2 mutant mouse line that expresses the N-terminal half (1–1295) of talin2 fused with β-galactosidase. The homozygous mutant mice appear to be normal and healthy. In the testis, talin2 expresses as a shorter form with a unique 30 residues at N-terminus linking to a common C-terminus from 1122 to 2453 of the long form. The resulting talin2 in the mutant testis only contains 204 residues of the wild-type testis talin2. However, it did not seem to affect the morphology of testis or reproduction of male mice. In fact, male and female mutant mice are fertile. Utilizing the expression of talin2(1–1295)/β-galactosidase fusion protein, we have examined the distribution of talin2 in tissues. In contrast to talin1, talin2 expression is more restricted in tissues and cell types. [Copyright &y& Elsevier]

Tensin is a cytoplasmic phosphoprotein that localized to integrin-mediated focal adhesions. It binds to actin filaments and contains a phosphotyrosine-binding (PTB) domain, which interacts with the cytoplasmic tails of β integrin. These interactions allow tensin to link actin filaments to integrin receptors. In addition, tensin has an Src Homology 2 (SH2) domain capable of interacting with tyrosine-phosphorylated proteins. Furthermore, several factors induce tyrosine phosphorylation of tensin. Thus, tensin functions as a platform for dis/assembly of signaling complexes at focal adhesions by recruiting tyrosine-phosphorylated signaling molecules through the SH2 domain, and also by providing interaction sites for other SH2-containing proteins. Analysis of knockout mice has demonstrated critical roles of tensin in renal function, muscle regeneration, and cell migration. Therefore, tensin and its downstream signaling molecules may be targets for therapeutic interventions in renal disease, wound healing and cancer. [Copyright &y& Elsevier]

Bone morphogenetic proteins (BMPs) induce cartilage differentiation and morphogenesis. There are profound changes in the cytoskeletal architecture during the morphogenesis of cartilage. To investigate the possibility that morphogenetic signals such as BMPs may regulate chondrocyte phenotype by modulation of cytoskeletal protein expression, we determined whether the expression and distribution of cytoskeletal proteins in chondrocytes are regulated by bone morphogenetic protein 7 (BMP 7), interleukin 1 (IL-1), and cellular context. Addition of BMP 7, a morphogen that induces chondrogenesis, to primary cultures of bovine and murine chondrocytes induced increased expression of four cytoskeletal proteins: tensin, talin, paxillin, and focal adhesion kinase (FAK). The expression of cytoskeletal proteins is dependent on cellular context; compared to monolayer, chondrocytes in suspension exhibited increased expression of cytoskeletal components. Conversely, addition of IL-1, a catabolic cytokine, induced loss of chondrocyte phenotype and decreased the expression of these cytoskeletal components. Treatment of chondrocytes with cytochalasin D (an agent that disrupts the actin cytoskeleton) inhibited BMP 7-induced upregulation of tensin, talin, paxillin, and FAK, and blocked the effect of BMP 7 on chondrocyte phenotype. Taken together these data demonstrate that cytoskeletal components play a critical role in the response to morphogens and cytokines in the regulation of chondrocyte phenotype. [Copyright &y& Elsevier]

Describes the interactions of tensin with actin and the identification of its three distinct actin-biding domains. Tensin as a phosphoprotein of focal contacts; Role of tensin in linking cell membrane to cytoskeleton; Direct response to tyrosine kinase signalling pathways.

DLC1 is a RhoGAP-containing tumor suppressor that inhibits angiogenesis by repressing VEGF production in epithelial cells. Here we report the roles of DLC1 in endothelial cells. Silencing of DLC1 (siDLC1) enhances cell migration but reduces tube formation activities of human umbilical vein endothelial cells (HUVECs). Biochemically, RhoA activity and paxillin protein level are markedly increased in siDLC1 HUVECs. Although further silencing of RhoA restores the cell migration phenotype, the tube formation defect and up-regulated paxillin level remain unchanged. On the other hand, paxillin knockdown rescues tube formation and migration phenotypes but not the up-regulated RhoA activity. These results indicate that DLC1 regulates endothelial cell migration through RhoA and paxillin independently and controls tube formation mainly via paxillin. To further determine endothelial DLC1's function, we have generated endothelial specific knockout mice (DLC1-Tek). DLC1-Tek mice appear to be normal and healthy but their angiogenesis processes are compromised as shown in gel plug and aortic ring sprouting assays. Analysis of endothelial cells isolated from DLC1-Tek mice has further affirmed the cellular and biochemical phenotypes established in siDLC1 HUVECs. Our studies have demonstrated a positive regulatory role of endothelial DLC1 in angiogenesis. [ABSTRACT FROM AUTHOR]

Abstract Spatial and temporal subcellular localization plays critical roles in regulating protein function. Cten (C-terminal tensin like) is a member of the tensin family. Cten recruits signaling molecules, such as DLC1, to focal adhesions, modulates homeostasis of receptor tyrosine kinases, including EGFR and c-Met, and promotes cell migration. These functions are likely controlled by Cten localization at focal adhesions and/or in the cytoplasm. In addition, Cten has been detected in the nucleus by which mechanism is unknown. To this end, we have examined the distribution of Cten in various cell lines, determined primary sequence requirements for its nuclear and focal adhesion localizations, and analyzed potential roles of nuclear Cten. Our results show that a proportion of Cten translocates to nuclei in cancer cell lines and that nuclear exporting of Cten is a CRM1-dependent process. A nuclear localization sequence and a nuclear export sequence are identified within Cten. In addition, like other tensins, Cten contains two independent focal adhesion binding sites. Although further expression of recombinant Cten showed no effect on cancer cell proliferation, silencing of Cten significantly reduced cell growth. Furthermore, expression of Cten mutants either with defective nuclear export sequence or tagged with SV40 nuclear localization sequence promoted cell growth. These results suggest that nuclear Cten contributes to cancer cell proliferation. Our findings identify a molecular mechanism for regulating Cten protein trafficking in mammalian cells and provide new insights into the dynamics of focal adhesion complexes in health and disease. Highlights • Cten shuttles between focal adhesion and nucleus. • Cten contains one nuclear localization sequence, one nuclear export sequence, and two focal adhesion binding regions. • Nuclear Cten promotes cancer cell proliferation. [ABSTRACT FROM AUTHOR]

DLC1 is a RhoGAP-containing tumor suppressor that inhibits angiogenesis by repressing VEGF production in epithelial cells. Here we report the roles of DLC1 in endothelial cells. Silencing of DLC1 (siDLC1) enhances cell migration but reduces tube formation activities of human umbilical vein endothelial cells (HUVECs). Biochemically, RhoA activity and paxillin protein level are markedly increased in siDLC1 HUVECs. Although further silencing of RhoA restores the cell migration phenotype, the tube formation defect and up-regulated paxillin level remain unchanged. On the other hand, paxillin knockdown rescues tube formation and migration phenotypes but not the up-regulated RhoA activity. These results indicate that DLC1 regulates endothelial cell migration through RhoA and paxillin independently and controls tube formation mainly via paxillin. To further determine endothelial DLC1's function, we have generated endothelial specific knockout mice (DLC1-Tek). DLC1-Tek mice appear to be normal and healthy but their angiogenesis processes are compromised as shown in gel plug and aortic ring sprouting assays. Analysis of endothelial cells isolated from DLC1-Tek mice has further affirmed the cellular and biochemical phenotypes established in siDLC1 HUVECs. Our studies have demonstrated a positive regulatory role of endothelial DLC1 in angiogenesis. [ABSTRACT FROM AUTHOR]

p63 is a member of the p53 transcription factor family and a linchpin of epithelial development and homeostasis. p63 drives the expression of many target genes involved in cell survival, adhesion, migration and cancer. In this study, we identify C-terminal tensin-like (CTEN) molecule as a downstream target of ΔNp63α, the predominant p63 isoform expressed in epithelium. CTEN belongs to the tensin family and is mainly localized to focal adhesions, which mediate many biological events such as cell adhesion, migration, proliferation and gene expression. Our study demonstrate that ΔNp63 and CTEN are both highly expressed in normal prostate epithelial cells and are down-regulated in prostate cancer. In addition, reduced expression of CTEN and ΔNp63 is correlated with prostate cancer progression from primary tumors to metastatic lesions. Silencing of ΔNp63 leads to decreased mRNA and protein levels of CTEN. ΔNp63α induces transcriptional activity of the CTEN promoter and a 140-bp fragment upstream of the transcription initiation site is the minimal promoter region required for activation. A putative binding site for p63 is located between -61 and -36 within the CTEN promoter and mutations of the critical nucleotides in this region abolish ΔNp63α-induced promoter activity. The direct interaction of ΔNp63α with the CTEN promoter was demonstrated using a chromatin immunoprecipitation (ChIP) assay. Moreover, impaired cell adhesion caused by ΔNp63α depletion is rescued by over-expression of CTEN, suggesting that CTEN is a downstream effector of ΔNp63α-mediated cell adhesion. In summary, our findings demonstrate that ΔNp63α functions as a trans-activation factor of CTEN promoter and regulates cell adhesion through modulating CTEN. Our study further contributes to the potential regulatory mechanisms of CTEN in prostate cancer progression. [ABSTRACT FROM AUTHOR]

DLC1 is a RhoGAP-containing tumor suppressor and many of DLC1's functions are absolutely dependent on its RhoGAP activity. Through its RhoGAP domain, DLC1 inhibits the activity of RhoA GTPase, which regulates actin cytoskeleton networks and dis/assembly of focal adhesions. Tensin1 (TNS1) is a focal adhesion molecule that links the actin cytoskeleton to integrins and forms signaling complexes through its multiple binding domains. Here, we report that TNS1 enhances RhoA activity in a DLC1-dependent manner. This is accomplished by binding to DLC1 through TNS1's C2, SH2, and PTB domains. Point mutations at these three sites disrupt TNS1's interaction with DLC1 as well as its effect on RhoA activity. The biological relevance of this TNS1–DLC1–RhoA signaling axis is investigated in TNS1 knockout (KO) cells and mice. Endothelial cells isolated from TNS1 KO mice or those silenced with TNS1 siRNA show significant reduction in proliferation, migration, and tube formation activities. Concomitantly, the RhoA activity is down-regulated in TNS1 KO cells and this reduction is restored by further silencing of DLC1. Furthermore, the angiogenic process is compromised in TNS1 KO mice. These studies demonstrate that TNS1 binds to DLC1 and fine-tunes its RhoGAP activity toward RhoA and that the TNS1–DLC1–RhoA signaling axis is critical in regulating cellular functions that lead to angiogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Cten is a focal adhesion molecule and a member of the tensin family. Its expression is highly enriched in the prostate and placenta, suggesting that cten gene might be closely associated with mammalian species. Recent studies have reported that cten expression is frequently up-regulated in a variety of cancers and its levels appear to correlate with tumorigenicity. Here, we have (1) analyzed cten sequences of various species to build a phylogenetic tree, (2) examined cten mRNA levels in human and mouse tissues to establish its expression profiles, and (3) determined the promoter region of human CTEN gene in cell lines and in a mouse model to understand its transcriptional regulation. Our analyses indicate that all currently known cten genes are present in mammals. The prostate and placenta are the two most cten abundant tissues in human and mouse, meanwhile brain and lung also express low levels of cten. Results from cell culture reporter assays demonstrate that a 327-bp fragment is the shortest functional promoter. All functional promoter constructs produce 40- to 160-fold increases in luciferase reporter activities in normal prostate cells, whereas lower activities (<40-fold) are detected in non-prostatic cell lines. To evaluate CTEN promoter activity in mice and develop a new tissue specific Cre recombinase mouse model, we have established pCTEN-Cre:R26R mice by crossing R26R β-galactosidase reporter mice with pCTEN-Cre transgenic mice, in which the 327-bp cten promoter drives the expression of Cre recombinase. X-gal analysis has shown strong β-galactosidase activities in the prostate, brain, and few other tissues in pCTEN-Cre:R26R mice. Altogether, we have identified the promoter region of human cten gene and provided a useful tool for investigating cell lineages and generating tissue-specific knockout or knockin mice. [Copyright &y& Elsevier]

Cell migration driven by the epidermal growth factor receptor (EGFR) propels morphogenesis and involves reorganization of the actin cytoskeleton. Although de novo transcription precedes migration, transcript identity remains largely unknown. Through their actin-binding domains, tensins link the cytoskeleton to integrin-based adhesion sites. Here we report that EGF downregulates tensin-3 expression, and concomitantly upregulates cten, a tensin family member that lacks the actin-binding domain. Knockdown of cten or tensin-3, respectively, impairs or enhances mammary cell migration. Furthermore, cten displaces tensin-3 from the cytoplasmic tail of integrin β1, thereby instigating actin fibre disassembly. In invasive breast cancer, cten expression correlates not only with high EGFR and HER2, but also with metastasis to lymph nodes. Moreover, treatment of inflammatory breast cancer patients with an EGFR/HER2 dual-specificity kinase inhibitor significantly downregulated cten expression. In conclusion, a transcriptional tensin-3–cten switch may contribute to the metastasis of mammary cancer. [ABSTRACT FROM AUTHOR]

The tensin family member cten (C-terminal tensin like) is an Src homology 2 (SH2) and phosphotyrosine binding domain--containing focal adhesion molecule that may function as a tumor suppressor. However, the mechanism has not been well established. We report that cten binds to another tumor suppressor, deleted in liver cancer 1 (DLC-1), and the SH2 domain of cten is responsible for the interaction. Unexpectedly, the interaction between DLC-1 and the cten SH2 domain is independent of tyrosine phosphorylation of DLC-1. By site-directed mutagenesis, we have identified several amino acid residues on cten and DLC-1 that are essential for this interaction. Mutations on DLC-1 perturb the interaction with cten and disrupt the focal adhesion localization of DLC-1. Furthermore, these DLC-1 mutants have lost their tumor suppression activities. When these DLC-1 mutants were fused to a focal adhesion targeting sequence, their tumor suppression activities were significantly restored. These results provide a novel mechanism whereby the SH2 domain of cten-mediated focal adhesion localization of DLC-1 plays an essential role in its tumor suppression activity. [ABSTRACT FROM AUTHOR]

Abstract: Tensin family is a group of focal adhesion proteins that interact with integrins, actin, and phosphotyrosine-containing proteins. To explore the in vivo functions of a new member of the family, tensin3, we have generated mutant mice with a disrupted tensin3 gene. Inactivation of tensin3 resulted in growth retardation and postnatal lethality in one third of the homozygous mutants. Histological analysis of those mutants showed incomplete development of the small intestine, lung, and bone. Villus formation in the small intestine was affected and cells migrated slower in the runt mutants. Their lungs also displayed enlarged air space suggesting defects in alveogenesis. In addition, the resting zone was thicker and fewer proliferating cells were present in the growth plates of tensin3−/− tibiae. These observations indicate that tensin3 is essential for normal development and functions of the small intestine, lung, and bone. These phenotypes of the runt tensin3−/− mice are similar to some clinical features of Silver–Russell syndrome (SRS) which is a genetically inherited defect. About 10% of SRS cases have been linked to abnormality in chromosome 7p11.2–13, where human tensin3 gene is located, suggesting a potential link between tensin3 and SRS. [Copyright &y& Elsevier]