A Phosphatidylinositol 3-Kinase-independent Insulin Signaling Pathway to N-WASP/Arp2/3/F-actin Required for GLUT4 Glucose Transporter Recycling

• Published in: The Journal of biological chemistry 2002-01, Vol.277 (1), p.509-515
• Main Authors: Jiang, Zhen Y., Chawla, Anil, Bose, Avirup, Way, Michael, Czech, Michael P.
• Format: Article
• Language: English
• Subjects: Actin-Related Protein 2; Actin-Related Protein 3; Actins - analysis; Actins - metabolism; Biological Transport; Cytoskeletal Proteins; Glucose Transporter Type 4; Humans; Insulin - pharmacology; Monosaccharide Transport Proteins - metabolism; Muscle Proteins; Nerve Tissue Proteins - analysis; Nerve Tissue Proteins - metabolism; Phosphatidylinositol 3-Kinases - physiology; Wiskott-Aldrich Syndrome Protein, Neuronal
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M108280200

Recruitment of intracellular glucose transporter 4 (GLUT4) to the plasma membrane of fat and muscle cells in response to insulin requires phosphatidylinositol (PI) 3-kinase as well as a proposed PI 3-kinase-independent pathway leading to activation of the small GTPase TC10. Here we show that in cultured adipocytes insulin causes acute cortical localization of the actin-regulatory neural Wiskott-Aldrich syndrome protein (N-WASP) and actin-related protein-3 (Arp3) as well as cortical F-actin polymerization by a mechanism that is insensitive to the PI 3-kinase inhibitor wortmannin. Expression of the dominant inhibitory N-WASP-ΔWA protein lacking the Arp and actin binding regions attenuates the cortical F-actin rearrangements by insulin in these cells. Remarkably, the N-WASP-ΔWA protein also inhibits insulin action on GLUT4 translocation, indicating dependence of GLUT4 recycling on N-WASP-directed cortical F-actin assembly. TC10 exhibits sequence similarity to Cdc42 and has been reported to bind N-WASP. We show the inhibitory TC10 (T31N) mutant, which abrogates insulin-stimulated GLUT4 translocation and glucose transport, also inhibits both cortical localization of N-WASP and F-actin formation in response to insulin. These findings reveal that N-WASP likely functions downstream of TC10 in a PI 3-kinase-independent insulin signaling pathway to mobilize cortical F-actin, which in turn promotes GLUT4 responsiveness to insulin.