CDK5-dependent phosphorylation of the Rho family GTPase TC10α regulates insulin-stimulated GLUT4 translocation

Shuichi Okada, Eijiro Yamada, Tsugumichi Saito, Kihachi Ohshima, Koshi Hashimoto, Masanobu Yamada, Yutaka Uehara, Takafumi Tsuchiya, Hiroyuki Shimizu, Kazuaki Tatei, Takashi Izumi, Keishi Yamauchi, Shin Ichi Hisanaga, Jeffrey E. Pessin, Masatomo Mori

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Insulin stimulation results in the activation of cyclin-dependent kinase-5 (CDK5) in lipid raft domains via a Fyn-dependent phosphorylation on tyrosine residue 15. In turn, activated CDK5 phosphorylates the Rho family GTP-binding protein TC10α on threonine 197 that is sensitive to the CDK5 inhibitor olomoucine and blocked by small interfering RNA-mediated knockdown of CDK5. The phosphorylation deficient mutant T197A-TC10α was not phosphorylated and excluded from the lipid raft domain, whereas the phosphorylation mimetic mutant (T197D-TC10α) was lipid raft localized. Insulin resulted in the GTP loading of T197D-TC10α but not T197A-TC10α and in parallel, T197D-TC10α but not T197A-TC10α depolymerized cortical actin and inhibited insulin-stimulated GLUT4 translocation. These data demonstrate that CDK5-dependent phosphorylation maintains TC10α in lipid raft compartments thereby disrupting cortical actin, whereas subsequent dephosphorylation of TC10α through inactivation of CDK5 allows for the re-assembly of F-actin. Because cortical actin reorganization is required for insulin-stimulated GLUT4 translocation, these data are consistent with a CDK5-dependent TC10α cycling between lipid raft and non-lipid raft compartments.

Original languageEnglish (US)
Pages (from-to)35455-35463
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number51
DOIs
StatePublished - Dec 19 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Okada, S., Yamada, E., Saito, T., Ohshima, K., Hashimoto, K., Yamada, M., Uehara, Y., Tsuchiya, T., Shimizu, H., Tatei, K., Izumi, T., Yamauchi, K., Hisanaga, S. I., Pessin, J. E., & Mori, M. (2008). CDK5-dependent phosphorylation of the Rho family GTPase TC10α regulates insulin-stimulated GLUT4 translocation. Journal of Biological Chemistry, 283(51), 35455-35463. https://doi.org/10.1074/jbc.M806531200