Role of Tensin3 during plasticity of cell adhesion
Final Report Abstract
A change regarding the extent of adhesion between adhesive and less-adhesive states is important for mammalian cell behavior such as migration. Optimal mesenchymal migration occurs upon intermediate adhesive strength and, most importantly, dynamic remodelling of cell matrix contacts. Typical components of such matrix contacts are the cytoplasmatic tensin proteins. We recently identified tensin 3 as a major determinant of cell morphology, adhesion and migration in MDA-MB 468 human breast cancer cells. However, it remained unclear how Tensin3 mechanistically affects focal adhesion dynamics and motility. Thus we aimed to elucidate the details and functional consequences of Tensin3-dependent adhesion of cancer cells. We generated various deletion and mutation constructs of tensin3 fused to EGFP and overexpressed them both transiently and stably in MDA-MB-468 cells. For characterization we performed fluorescence microscopy, live imaging and impedance-based real time cell analysis. Experiments showed that constructs lacking the tensin 3-specific central region lead to a mislocalization of tensin3 and paxillin. Our results demonstrated a previously unexpected critical role for this intrinsically disordered region of tensin 3. Deletion constructs of this region were mislocalised throughout the cell body, less prominently found in the cell cortex, and the overexpressing cells showed lower cortical actin but more stress fibers. In addition, cell motility and spreading was impaired compared to control cells. Our preliminary results were recently confirmed by independent findings, showing that tensin 3 contributes to the formation of fibrillar adhesions in osteosarcoma cells. Here, tensin 3 associates with the mechanosensors talin and vinculin via the central intrinsically disordered region of tensin 3. This interaction was shown to be critical for the formation of integrin-linked fibrillar adhesions and migration. Their findings suggested that a similar mechanism is also involved in the IDR-dependent function of tensin 3 in our system.
Publications
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A dual phenotype of MDA-MB-468 cancer cells reveals mutual regulation of tensin3 and adhesion plasticity. Journal of Cell Science, 130(13), 2172-2184.
Veß, Astrid; Blache, Ulrich; Leitner, Laura; Kurz, Angela R. M.; Ehrenpfordt, Anja; Sixt, Michael & Posern, Guido
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Post-transcriptional regulation of MRTF-A by miRNAs during myogenic differentiation of myoblasts. Nucleic Acids Research, 48(16), 8927-8942.
Holstein, Ingo; Singh, Anurag Kumar; Pohl, Falk; Misiak, Danny; Braun, Juliane; Leitner, Laura; Hüttelmaier, Stefan & Posern, Guido
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miRNA mediated downregulation of cyclase-associated protein 1 (CAP1) is required for myoblast fusion. Frontiers in Cell and Developmental Biology, 10.
Singh, Anurag Kumar; Rai, Amrita; Weber, Anja & Posern, Guido
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MRTF-A gain-of-function in mice impairs homeostatic renewal of the intestinal epithelium. Cell Death & Disease, 14(9).
Singh, Anurag Kumar; Rai, Amrita; Weber, Anja; Gericke, Martin; Janssen, Klaus-Peter; Moser, Markus & Posern, Guido
