1. Cancer associated talin point mutations disorganise cell adhesion and migration
- Author
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Latifeh Azizi, Vesa P. Hytönen, Benjamin T. Goult, Paula Turkki, Vasyl V. Mykuliak, Alana R Cowell, Tampere University, BioMediTech, and Department of Clinical Chemistry
- Subjects
Talin ,animal structures ,Somatic cell ,Science ,Integrin ,Mutant ,macromolecular substances ,medicine.disease_cause ,environment and public health ,Article ,03 medical and health sciences ,Cell Movement ,Neoplasms ,Databases, Genetic ,medicine ,Humans ,Point Mutation ,Cell migration ,Cell adhesion ,Cancer genetics ,Actin ,QH581.2 ,030304 developmental biology ,0303 health sciences ,Mutation ,biology ,Chemistry ,Point mutation ,030302 biochemistry & molecular biology ,Computational Biology ,Computational biology and bioinformatics ,Cell biology ,Mechanisms of disease ,Cell polarity ,embryonic structures ,biology.protein ,Medicine ,3111 Biomedicine ,biological phenomena, cell phenomena, and immunity ,Cell signalling - Abstract
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.
- Published
- 2021