Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10.
The stimulation of glucose uptake by insulin in muscle and adipose tissue requires translocation of the GLUT4 glucose transporter protein from intracellular storage sites to the cell surface. Although the cellular dynamics of GLUT4 vesicle trafficking are well described, the signalling pathways that link the insulin receptor to GLUT4 translocation remain poorly understood. Activation of phosphatidylinositol-3-OH kinase (PI(3)K) is required for this trafficking event, but it is not sufficient to produce GLUT4 translocation. We previously described a pathway involving the insulin-stimulated tyrosine phosphorylation of Cbl, which is recruited to the insulin receptor by the adapter protein CAP. On phosphorylation, Cbl is translocated to lipid rafts. Blocking this step completely inhibits the stimulation of GLUT4 translocation by insulin. Here we show that phosphorylated Cbl recruits the CrkII-C3G complex to lipid rafts, where C3G specifically activates the small GTP-binding protein TC10. This process is independent of PI(3)K, but requires the translocation of Cbl, Crk and C3G to the lipid raft. The activation of TC10 is essential for insulin-stimulated glucose uptake and GLUT4 translocation. The TC10 pathway functions in parallel with PI(3)K to stimulate fully GLUT4 translocation in response to insulin.
Chiang
S H
SH
Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, Michigan 48105, USA.
Baumann
C A
CA
Kanzaki
M
M
Thurmond
D C
DC
Watson
R T
RT
Neudauer
C L
CL
Macara
I G
IG
Pessin
J E
JE
Saltiel
A R
AR
D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D020735:Guanine Nucleotide-Releasing Factor 2 / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D050737:Proto-Oncogene Proteins c-crk; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D020735:Guanine Nucleotide-Releasing Factor 2; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D011993:Recombinant Fusion Proteins; C495693:Slc2a4 protein, mouse; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; C503260:Rhoq protein, mouse; D020764:cdc42 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; C493849:Cbl protein, mouse; D005947:Glucose