TCGAP, a multidomain Rho GTPase-activating protein involved in insulin-stimulated glucose transport.
Insulin stimulates glucose uptake in fat and muscle cells via the translocation of the GLUT4 glucose transporter from intracellular storage vesicles to the cell surface. The signaling pathways linking the insulin receptor to GLUT4 translocation in adipocytes involve activation of the Rho family GTPases TC10alpha and beta. We report here the identification of TCGAP, a potential effector for Rho family GTPases. TCGAP consists of N-terminal PX and SH3 domains, a central Rho GAP domain and multiple proline-rich regions in the C-terminus. TCGAP specifically interacts with cdc42 and TC10beta through its GAP domain. Although it has GAP activity in vitro, TCGAP is not active as a GAP in intact cells. TCGAP translocates to the plasma membrane in response to insulin in adipocytes. The N-terminal PX domain interacts specifically with phos phatidylinositol-(4,5)-bisphosphate. Overexpression of the full-length and C-terminal fragments of TCGAP inhibits insulin-stimulated glucose uptake and GLUT4 translocation. Thus, TCGAP may act as a downstream effector of TC10 in the regulation of insulin-stimulated glucose transport.
Chiang
Shian-Huey
SH
Life Sciences Institute, Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109-0650, USA.
Hwang
Joseph
J
Legendre
Marie
M
Zhang
Mei
M
Kimura
Akiko
A
Saltiel
Alan R
AR
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D016466:CHO Cells; D019556:COS Cells; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003001:Cloning, Molecular; D006224:Cricetinae; D018076:DNA, Complementary / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050737:Proto-Oncogene Proteins c-crk; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058305:Sorting Nexins; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
C475477:ARHGAP33 protein, human; D018076:DNA, Complementary; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D011994:Recombinant Proteins; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; D058305:Sorting Nexins; C475478:TCGAP protein, mouse; C085379:rho GTPase-activating protein; C503256:RHOQ protein, human; C503260:Rhoq protein, mouse; D020764:cdc42 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D005947:Glucose