The insulin and the endothelin type-A (ETA) receptor both can couple into the heterotrimeric G protein-q/11 (Gq/11), leading to Gq/11 tyrosine phosphorylation, PI3-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, Gq/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 Gq/11 tyrosine phosphorylation and GLUT4 translocation. In co-immunoprecipitation experiments, we found that -arrestin 1 associated with the ETA receptor in an agonist dependent manner, and that -arrestin 1 recruited Src kinase to a molecular complex which included the ETA receptor. Microinjection of -arrestin 1 antibody inhibited ET-1, but not insulin, stimulated GLUT4 translocation. In conclusion, 1) the Src-kinase Yes can induce tyrosine phosphorylation of Gq/11 in response to ET-1 stimulation, and 2) -arrestin 1 and Src-kinase form a molecular complex with the ETA receptor to mediate ET-1 signaling to Gq/11 with subsequent glucose transport stimulation.