beta -Arrestin-mediated recruitment of the Src family kinase Yes mediates endothelin-1-stimulated glucose transport.
The insulin and the endothelin type A (ETA) receptor both can couple into the heterotrimeric G protein alpha(q/11) (Galpha(q/11)), leading to Galpha(q/11) tyrosine phosphorylation, phosphatidylinositol 3-kinase activation, and subsequent stimulation of glucose transport. In this study, we assessed the potential role of Src kinase in ET-1 signaling to glucose transport ... in 3T3-L1 adipocytes. Src kinase inhibitor PP2 blocked ET-1-induced Src kinase activity, Galpha(q/11) tyrosine phosphorylation, and glucose transport stimulation. To determine which Src family kinase member was involved, we microinjected anti-c-Src, -c-Fyn, or -c-Yes antibody into these cells and found that only anti-c-Yes antibody blocked GLUT4 translocation (70% decreased). Overexpression or microinjection of a dominant negative mutant (K298M) of Src kinase also inhibited ET-1-induced Galpha(q/11) tyrosine phosphorylation and GLUT4 translocation. In co-immunoprecipitation experiments, we found that beta-arrestin 1 associated with the ETA receptor in an agonist-dependent manner and that beta-arrestin 1 recruited Src kinase to a molecular complex that included the ETA receptor. Microinjection of beta-arrestin 1 antibody inhibited ET-1- but not insulin-stimulated GLUT4 translocation. In conclusion, 1) the Src kinase Yes can induce tyrosine phosphorylation of Galpha(q/11) in response to ET-1 stimulation, and 2) beta-arrestin 1 and Src kinase form a molecular complex with the ETA receptor to mediate ET-1 signaling to Galpha(q/11) with subsequent glucose transport stimulation.
Mesh Terms:
3T3 Cells, Animals, Arrestins, Biological Transport, Endothelin-1, GTP-Binding Protein alpha Subunits, Gq-G11, Glucose, Glucose Transporter Type 4, Heterotrimeric GTP-Binding Proteins, Mice, Microscopy, Fluorescence, Monosaccharide Transport Proteins, Muscle Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-yes, Signal Transduction, src-Family Kinases
3T3 Cells, Animals, Arrestins, Biological Transport, Endothelin-1, GTP-Binding Protein alpha Subunits, Gq-G11, Glucose, Glucose Transporter Type 4, Heterotrimeric GTP-Binding Proteins, Mice, Microscopy, Fluorescence, Monosaccharide Transport Proteins, Muscle Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-yes, Signal Transduction, src-Family Kinases
J. Biol. Chem.
Date: Nov. 23, 2001
PubMed ID: 11546805
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