Talin-1 Gene Expression as a Tumor Marker in Hepatocellular Carcinoma Patients: A Pilot Study

Mohamed, Azah; El-Toukhy, Naglaa; Ghaith, Doaa; Badawy, Ingy; Abdo, Sara M.; Elkadeem, Mahmoud; Mahrous, Mohamed N.

doi:10.2174/1875318302010010015

Cited by 6 publications

(2 citation statements)

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“…Investigation of the contribution of talin to cancer progression is timely. During this study ~ 670 more cancer-associated talin-1 point mutations have been added to the COSMIC database ( Supplementary Fig.S1) and there are recent studies discussing the connection between talin and cancer 23,[55][56][57][58] . The work we present here demonstrates an efficient and fast pipeline approach using bioinformatics tools to characterise future talin mutations identified in cancer and other diseases.…”

Section: Discussionmentioning

confidence: 99%

Cancer associated talin point mutations disorganise cell adhesion and migration

Azizi

Cowell

Mykuliak

et al. 2021

Sci Rep

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Talin-1 is a key component of the multiprotein adhesion complexes which mediate cell migration, adhesion and integrin signalling and has been linked to cancer in several studies. We analysed talin-1 mutations reported in the Catalogue of Somatic Mutations in Cancer database and developed a bioinformatics pipeline to predict the severity of each mutation. These predictions were then assessed using biochemistry and cell biology experiments. With this approach we were able to identify several talin-1 mutations affecting integrin activity, actin recruitment and Deleted in Liver Cancer 1 localization. We explored potential changes in talin-1 signalling responses by assessing impact on migration, invasion and proliferation. Altogether, this study describes a pipeline approach of experiments for crude characterization of talin-1 mutants in order to evaluate their functional effects and potential pathogenicity. Our findings suggest that cancer related point mutations in talin-1 can affect cell behaviour and so may contribute to cancer progression.

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Section: Discussionmentioning

confidence: 99%

Cancer associated talin point mutations disorganise cell adhesion and migration

Azizi

Cowell

Mykuliak

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Talin-1 is a key component of the multiprotein adhesion complexes which mediate cell migration, adhesion and integrin signalling and has been linked to cancer in several studies. We analysed talin-1 mutations reported in the Catalogue of Somatic Mutations in Cancer database and developed a bioinformatics pipeline to predict the severity of each mutation. These predictions were then assessed using biochemistry and cell biology experiments. With this approach we were able to identify several talin-1 mutations affecting integrin activity, actin recruitment and Deleted in Liver Cancer 1 localization. We explored potential changes in talin-1 signalling responses by assessing impact on migration, invasion and proliferation. Altogether, this study describes a pipeline approach of experiments for crude characterization of talin-1 mutants in order to evaluate their functional effects and potential pathogenicity. Our findings suggest that cancer related point mutations in talin-1 can affect cell behaviour and so may contribute to cancer progression.

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“…there are recent studies discussing the connection between talin and cancer 23,[55][56][57][58] . The work we present here demonstrates an efficient and fast pipeline approach using bioinformatics tools to characterise future talin mutations identified in cancer and other diseases.…”

Section: Discussionmentioning

confidence: 99%

Cancer associated talin point mutations disorganise cell adhesion and migration

Azizi

Cowell

Mykuliak

et al. 2020

Preprint

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Talin-1 is a key component of the multiprotein adhesion complexes which mediate cell migration, adhesion and integrin signalling and has been linked to cancer in several studies. In this study we analysed mutations in talin-1 reported in the Catalogue of Somatic Mutations in Cancer. A total of 11 talin mutants were selected and expressed in talin-deficient fibroblasts and their functional and structural effects were characterised in detail. An I392N point mutation in the F3 domain caused a three-fold increase in invasion, and enhanced migration compared to wildtype talin. Mutations R1368W and L1539P in the R7 and R8 domains caused increased invasion and proliferation and affected talin-vinculin complexation, but were not linked to changes in their binding affinities with known substrates KANK1 and RIAM measured for isolated talin domains. Lastly, L2509P, a mutation in the dimerisation domain of talin, prevented talin dimer formation, actin recruitment and FAKpTyr397 activation leading to anisotropic cell spreading and loss of random migration. Altogether, this study suggests that cancer derived point mutations in talin-1 can drastically affect cell behaviour and so may contribute to cancer progression. , I. L. et al. (2015). Vinculin controls talin engagement with the actomyosin machinery. Nat. Commun. 6, 10038. (2017). Downregulation of Talin1 promotes hepatocellular carcinoma progression through activation of the ERK1/2 pathway. Leinonen, R., Shumway, M. et al. (2012). The 1000 genomes project: Data management and community access. Nat. Methods 9, 459-462. (2009). Stretching single talin rod molecules activates vinculin binding. Science 323, 638-641. Dupont, S., Morsut, L., Aragona, M., Enzo, E., Giulitti, S., Cordenonsi, M., Zanconato, F., Le Digabel, J., Forcato, M., Bicciato, S. et al. (2011). Role of YAP/TAZ in mechanotransduction. Nature 474, 179-183. Kim, N. G. and Gumbiner, B. M. (2015). Adhesion to fibronectin regulates hippo signaling via the FAK-src-PI3K pathway. A. R. et al. (2010). Studies on the morphology and spreading of human endothelial cells define key inter-and intramolecular interactions for talin1. Eur. J. Cell Biol. 89, 661-673. . (2016). Talin tension sensor reveals novel features of focal adhesion force transmission and mechanosensitivity. Guichard, S. et al. (2016). Rho-associated kinase (ROCK) function is essential for cell cycle progression, senescence and tumorigenesis. Elife 5, e12994. . (2011). Talin-1 overexpression defines high risk foraggressive oral squamous cell carcinoma and promotes cancer metastasis. . (2010). Improved side-chain torsion potentials for the amber ff99SB protein force field.Proteins 78, 1950-1958.

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