Cloning and Functional Characterization of Related TC10 Isoforms, a Subfamily of Rho Proteins Involved in Insulin-stimulated Glucose Transport

Abstract

Insulin stimulates glucose transport via phosphatidylinositol 3-kinase-dependent and -independent pathways. The phosphatidylinositol 3-kinase-independent pathway involves activation of the G protein TC10. A cDNA encoding the mouse homolog of TC10 was cloned, and its gene was mapped at the distal end of chromosome 17. Additionally, a second gene was discovered with ϳ70% sequence identity to TC10. We refer to this gene as TC10␤. Both isoforms of TC10 were activated by insulin upon transfection in 3T3L1 adipocytes. Cotransfection of cells with TC10␣ or ␤ plus a dominant negative form of the c-cbl-associated protein CAP prevented the activation by insulin, implicating the CAP/Cbl pathway. Interestingly, both forms of TC10 were also localized in lipid raft fractions in transfected adipocytes. However, although overexpression of TC10␣ completely blocked glucose transport, TC10␤ only partially inhibited this process. Furthermore, TC10␣ overexpression disrupted adipocyte cortical actin, whereas TC10␤ had little if any effect. Thus, there are two isoforms of this key signaling intermediate, both of which are activated by insulin, but they may play different roles in initiating downstream effectors that influence glucose transport.

Golgin-160 Is Required for the Golgi Membrane Sorting of the Insulin-responsive Glucose Transporter GLUT4 in Adipocytes

“…PIST has been reported to interact with the TGN Q-SNARE Stx6 that has also been suggested to be involved in the TGN sorting of GLUT4 (Charest et al, 2001;Perera et al, 2003;Shewan et al, 2003). Moreover, PIST was found to interact with the small Rho family GTP binding protein TC10 that has also been implicated in the insulin-regulated trafficking of GLUT4 Neudauer et al, 2001;Chiang et al, 2002).…”

“…PIST has been reported to interact with the TGN Q-SNARE Stx6 that has also been suggested to be involved in the TGN sorting of GLUT4 (Charest et al, 2001;Perera et al, 2003;Shewan et al, 2003). Moreover, PIST was found to interact with the small Rho family GTP binding protein TC10 that has also been implicated in the insulin-regulated trafficking of GLUT4 Neudauer et al, 2001;Chiang et al, 2002).Our data clearly demonstrate that golgin-160 is required for the intracellular sequestration of endogenous as well as Once at the plasma membrane, endocytosis and recycling result in the trafficking back to the Golgi/TGN and retention in the IRC. In the absence of golgin-160 function, the GLUT4 and IRAP proteins default to the plasma membrane, bypassing the GGA-dependent sorting to the IRC.…”

Identification of P-Rex1 as a Novel Rac1-Guanine Nucleotide Exchange Factor (GEF) That Promotes Actin Remodeling and GLUT4 Protein Trafficking in Adipocytes

“…Cdc42 exhibits 69% amino acid homology and 86% similarity to the related small GTPase TC10 (58). TC10 activation is essential for maximal insulin-stimulated glucose transport; however, constitutively active TC10 paradoxically inhibits insulin-stimulated glucose transport (59), and this may also be the case for constitutively active Cdc42. Remodeling of the cortical actin network by TC10 is required for efficient GLUT4 translocation.…”

The activation of TC10, a Rho small GTPase, contributes to v-Rel-mediated transformation

“…TC10 has been cloned from vertebrates (human, mouse and rat), but is not present in budding yeast, suggesting that TC10 only functions in differentiated cells (Drivas et al, 1990;Neudauer et al, 1998;Tanabe et al, 2000;Chiang et al, 2002). TC10 is predominantly localized on the plasma and endosomal membranes ) and has been implicated in various biological functions.…”