A phosphatidylinositol 3-kinase-independent insulin signaling pathway to N-WASP/Arp2/3/F-actin required for GLUT4 glucose transporter recycling

UMMS Affiliation

Program in Molecular Medicine

Publication Date


Document Type



1-Phosphatidylinositol 3-Kinase; Actin-Related Protein 2; Actin-Related Protein 3; Actins; Biological Transport; *Cytoskeletal Proteins; Glucose Transporter Type 4; Humans; Insulin; Monosaccharide Transport Proteins; *Muscle Proteins; Nerve Tissue Proteins; Wiskott-Aldrich Syndrome Protein, Neuronal


Life Sciences | Medicine and Health Sciences


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-DeltaWA protein lacking the Arp and actin binding regions attenuates the cortical F-actin rearrangements by insulin in these cells. Remarkably, the N-WASP-DeltaWA 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.

DOI of Published Version



J Biol Chem. 2002 Jan 4;277(1):509-15. Epub 2001 Nov 1. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of biological chemistry

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PubMed ID