PathwayStep6447 PathwayStep6434 PathwayStep6435 PathwayStep6439 PathwayStep6438 PathwayStep6437 PathwayStep6436 PathwayStep6441 PathwayStep6442 PathwayStep6440 PathwayStep6445 PathwayStep6446 PathwayStep6443 PathwayStep6444 AMPK-alpha2 Phosphorylates TBC1D1 14-3-3 Binds Phosphorylated AS160 (TBC1D4) AKT1/2 Phosphorylates AS160 (TBC1D4) RAB4A:GTP Activates KIF3 14-3-3 Binds Phosphorylated TBC1D1 RAB8A/10/13/14 Exchange GDP for GTP RALA Hydrolyzes GTP AKT2 Phosphorylates Myosin 5A Translocation of GLUT4 Vesicle and Docking at the Plasma Membrane Fusion of GLUT4 Vesicle with the Plasma Membrane RAB8A/10/13/14 Hydrolyze GTP AKT2 Phosphorylates RGC2 Activation of RALA RALA:GTP Activates MYO1C Translocation of GLUT4 to the Plasma Membrane Authored: May, B, 2011-07-07 Edited: May, B, 2011-07-07 In adipocytes and myocytes insulin signaling causes intracellular vesicles carrying the GLUT4 glucose transporter to translocate to the plasma membrane, allowing the cells to take up glucose from the bloodstream (reviewed in Zaid et al. 2008, Leney and Tavare 2009, Bogan and Kandror 2010, Foley et al. 2011, Hoffman and Elmendorf 2011, Kandror and Pilch 2011). In myocytes muscle contraction alone can also cause translocation of GLUT4.<br>Though the entire pathway leading to GLUT4 translocation has not been elucidated, several steps are known. Insulin activates the kinases AKT1 and AKT2. Muscle contraction activates the kinase AMPK-alpha2 and possibly also AKT. AKT2 and, to a lesser extent, AKT1 phosphorylate the RAB GTPase activators TBC1D1 and TBC1D4, causing them to bind 14-3-3 proteins and lose GTPase activation activity. As a result RAB proteins (probably RAB8A, RAB10, RAB14 and possibly RAB13) accumulate GTP. The connection between RAB:GTP and vesicle translocation is unknown but may involve recruitment and activation of myosins.<br>Myosins 1C, 2A, 2B, 5A, 5B have all been shown to play a role in translocating GLUT4 vesicles near the periphery of the cell. Following docking at the plasma membrane the vesicles fuse with the plasma membrane in a process that depends on interaction between VAMP2 on the vesicle and SNAP23 and SYNTAXIN-4 at the plasma membrane. Pubmed18570632 Pubmed19389739 Pubmed20417083 Pubmed21216617 Pubmed21306486 Pubmed21405107 Reactome Database ID Release 431445148 Reactome, http://www.reactome.org ReactomeREACT_147867 Reviewed: Klip, Amira, 2012-08-21