Journal
BIOCHEMICAL JOURNAL
Volume 445, Issue -, Pages 323-332Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20112169
Keywords
actin dynamics; cofilin; Crk-associated substrate (p130Cas); integrin; megakaryocytic acute leukaemia (MAL); myogenic differentiation
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Funding
- Ministry of Education [R-154-000-406-112, R-154-000-430-112]
- Biomedical Research Council [R-154-000-423-305]
- Mechanobiology Institute, Singapore
- Grants-in-Aid for Scientific Research [24570191, 23689027] Funding Source: KAKEN
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Actin dynamics are implicated in various cellular processes, not only through the regulation of cytoskeletal organization, but also via the control of gene expression. In the present study we show that the Sic family kinase substrate p130Cas (Cas is Crk-associated substrate) influences actin remodelling and concomitant muscle-specific gene expression, thereby regulating myogenic differentiation. In C2C12 myoblasts, silencing of p130Cas expression by RNA interference impaired F-actin (filamentous actin) formation and nuclear localization of the SRF (serum-response factor) co-activator MAL (megakaryocytic acute leukaemia) following the induction of myogenic differentiation. Consequently, formation of multinucleated myotubes was abolished. Reintroduction of wild-type p130Cas, but not its phosphorylation-defective mutant, into p130Cas-knockdown myoblasts restored F-actin assembly, MAL nuclear localization and myotube formation. Depletion of the adhesion molecule integrin beta 3, a key regulator of myogenic differentiation as well as actin cytoskeletal organization, attenuated p130Cas phosphorylation and MAL nuclear localization during C2Cl2 differentiation. Moreover, knockdown of p130Cas led to the activation of the F-actin-severing protein cofilin. The introduction of a dominant-negative mutant of cofilin into p130Cas-knockdown myoblasts restored muscle-specific gene expression and myotube formation. The results of the present study suggest that p130Cas phosphorylation, mediated by integrin beta 3, facilitates cofilin inactivation and promotes myogenic differentiation through modulating actin cytoskeleton remodelling.
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