The roles of Cbl-b and c-Cbl in insulin-stimulated glucose transport.
Previous studies suggest that the stimulation of glucose transport by insulin involves the tyrosine phosphorylation of c-Cbl and the translocation of the c-Cbl/CAP complex to lipid raft subdomains of the plasma membrane. We now demonstrate that Cbl-b also undergoes tyrosine phosphorylation and membrane translocation in response to insulin in 3T3-L1 adipocytes. Ectopic expression of APS facilitated insulin-stimulated phosphorylation of tyrosines 665 and 709 in Cbl-b. The phosphorylation of APS produced by insulin drove the translocation of both c-Cbl and Cbl-b to the plasma membrane. Like c-Cbl, Cbl-b associates constitutively with CAP and interacts with Crk upon insulin stimulation. Cbl proteins formed homo- and heterodimers in vivo, which required the participation of a conserved leucine zipper domain. A Cbl mutant incapable of dimerization failed to interact with APS and to undergo tyrosine phosphorylation in response to insulin, indicating an essential role of Cbl dimerization in these processes. Thus, both c-Cbl and Cbl-b can initiate a phosphatidylinositol 3-kinase/protein kinase B-independent signaling pathway critical to insulin-stimulated GLUT4 translocation.
Liu
Jun
J
Departments of Internal Medicine and Physiology, Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
DeYoung
Stephanie M
SM
Hwang
Joseph B
JB
O'Leary
Erin E
EE
Saltiel
Alan R
AR
D048868:Adaptor Proteins, Signal Transducing; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D002352:Carrier Proteins / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D019281:Dimerization; D018274:Electroporation; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D013347:Subcellular Fractions; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C118387:Cblb protein, mouse; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C495693:Slc2a4 protein, mouse; D014443:Tyrosine; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; C493849:Cbl protein, mouse; D005947:Glucose