title: Rac-1 superactivation triggers insulin-independent glucose transporter 4 (GLUT4) translocation that bypasses signaling defects exerted by c-Jun N-terminal kinase (JNK)- and ceramide-induced insulin resistance.
abstract: Insulin activates a cascade of signaling molecules, including Rac-1, Akt, and AS160, to promote the net gain of glucose transporter 4 (GLUT4) at the plasma membrane of muscle cells. Interestingly, constitutively active Rac-1 expression results in a hormone-independent increase in surface GLUT4; however, the molecular mechanism and significance behind this effect remain unresolved. Using L6 myoblasts stably expressing myc-tagged GLUT4, we found that overexpression of constitutively active but not wild-type Rac-1 sufficed to drive GLUT4 translocation to the membrane of comparable magnitude with that elicited by insulin. Stimulation of endogenous Rac-1 by Tiam1 overexpression elicited a similar hormone-independent gain in surface GLUT4. This effect on GLUT4 traffic could also be reproduced by acutely activating a Rac-1 construct via rapamycin-mediated heterodimerization. Strategies triggering Rac-1 "superactivation" (i.e. to levels above those attained by insulin alone) produced a modest gain in plasma membrane phosphatidylinositol 3,4,5-trisphosphate, moderate Akt activation, and substantial AS160 phosphorylation, which translated into GLUT4 translocation and negated the requirement for IRS-1. This unique signaling capacity exerted by Rac-1 superactivation bypassed the defects imposed by JNK- and ceramide-induced insulin resistance and allowed full and partial restoration of the GLUT4 translocation response, respectively. We propose that potent elevation of Rac-1 activation alone suffices to drive insulin-independent GLUT4 translocation in muscle cells, and such a strategy might be exploited to bypass signaling defects during insulin resistance.
authors: Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors: Tim Ting
authors: TT
authors: Chiu
authors: Yi
authors: Y
authors: Sun
authors: Alexandra
authors: A
authors: Koshkina
authors: Amira
authors: A
authors: Klip
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D016764:Cell Polarity; D004789:Enzyme Activation; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D051275:Glucose Transporter Type 4; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; C064769:N-acetylsphingosine; D009363:Neoplasm Proteins; D010716:Phosphatidylinositols; C495694:Slc2a4 protein, rat; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513259:Tiam1 protein, rat; C118303:phosphoinositide-3,4,5-triphosphate; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; D013110:Sphingosine
keywords: AS160; Akt; Ceramide; Glut4; Insulin Resistance; Jun N-terminal Kinase (JNK); Rac1
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