The actin-related p41ARC subunit contributes to p21-activated kinase-1 (PAK1)-mediated glucose uptake into skeletal muscle cells

Ragadeepthi Tunduguru, Jing Zhang, Arianne Aslamy, Vishal A. Salunkhe, Joseph T. Brozinick, Jeffrey S. Elmendorf, Debbie C. Thurmond

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Defects in translocation of the glucose transporterGLUT4are associated with peripheral insulin resistance, preclinical diabetes, and progression to type 2 diabetes. GLUT4 recruitment to the plasma membrane of skeletal muscle cells requires F-actin remodeling. Insulin signaling in muscle requires p21-activated kinase-1 (PAK1), whose downstream signaling triggers actin remodeling, which promotesGLUT4vesicle translocation and glucose uptake into skeletal muscle cells. Actin remodeling is a cyclic process, and although PAK1 is known to initiate changes to the cortical actin-binding protein cofilin to stimulate the depolymerizing arm of the cycle, how PAK1 might trigger the polymerizing arm of the cycle remains unresolved. Toward this, we investigated whether PAK1 contributes to the mechanisms involving the actinbinding and -polymerizing proteins neural Wiskott-Aldrich syndrome protein (N-WASP), cortactin, and ARP2/3 subunits. We found that the actin-polymerizing ARP2/3 subunit p41ARC is a PAK1substrate in skeletalmusclecells. Moreover,co-immunoprecipitation experiments revealed that insulin stimulates p41ARC phosphorylation and increases its association with N-WASP coordinately with the associations ofN-WASPwith cortactin and actin. Importantly, all of these associations were ablated by the PAK inhibitor IPA3, suggesting that PAK1 activation lies upstream of these actin-polymerizing complexes. Using theN-WASPinhibitor wiskostatin,wefurther demonstrated thatN-WASPis required for localized F-actin polymerization, GLUT4 vesicle translocation, and glucose uptake. These results expand the model of insulinstimulated glucose uptake in skeletal muscle cells by implicating p41ARC as a new component of the insulin-signaling cascade and connecting PAK1 signaling to N-WASP-cortactin-mediated actin polymerization and GLUT4 vesicle translocation.

Original languageEnglish (US)
Pages (from-to)19034-19043
Number of pages10
JournalJournal of Biological Chemistry
Issue number46
StatePublished - Nov 17 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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