Src phosphorylates Grb2-associated binder 1 upon hepatocyte growth factor stimulation.
Grb2-associated binder 1 (Gab1) is known to play an important role in hepatocyte growth factor (HGF) signaling, which rapidly becomes tyrosine-phosphorylated upon HGF stimulation. In this study, we found that the tyrosine phosphorylation of Gab1 in the cells derived from Src/Yes/Fyn null mouse embryos was approximately 40% lower than that in their wild type counterparts upon HGF stimulation. Increased expression of wild-type Src enhanced HGF-induced phosphorylation of Gab1, and, in contrast, expression of the Src kinase-deficient mutant or treatment of the specific Src inhibitor PP1 suppressed it. Expression of a constitutively active Src mutant (Y527F) or oncogenic v-Src led to a prominent increase in Gab1 phosphorylation independent of HGF stimulation. Moreover, Src interacted with Gab1 via both its Src homology 2 and 3 domains and was capable of phosphorylating purified Gab1 in vitro. Finally, the increased phosphorylation of Gab1 by Src selectively potentiated HGF-induced activation of ERK and AKT. Taken together, our results establish a new role for Src in HGF-induced Gab1 phosphorylation.
Chan
Po-Chao
PC
Department of Life Sciences and the Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan.
Chen
Yen-Ling
YL
Cheng
Chi-Hung
CH
Yu
Kuo-Ching
KC
Cary
Leslie A
LA
Shu
Kuo-Hsiung
KH
Ho
William L
WL
Chen
Hong-Chen
HC
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004285:Dogs; D004357:Drug Synergism; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007668:Kidney; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; C098587:GAB1 protein, human; C490897:Gab1 protein, mouse; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; D019061:src-Family Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases