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Papers In Press, published online ahead of print April 8, 2002
Center for Cardiovascular Research, University of Rochester, Rochester, NY 14642
Corresponding Author: bradford_berk{at}urmc.rochester.edu
Grb2-associated binder-1 (Gab1) is an adapter protein related to the IRS-family. It is a substrate for the insulin receptor, as well as the epidermal growth factor (EGF) receptor and other receptor-tyrosine kinases. To investigate the role of Gab1 in signaling pathways downstream of growth factor receptors, we stimulated rat aortic vascular smooth muscle cells (VSMC) with EGF and platelet-derived growth factor (PDGF). Gab1 was tyrosine-phosphorylated by EGF and PDGF within 1 minute. AG1478 (EGF receptor kinase specific inhibitor) failed to block PDGF-induced Gab1 tyrosine-phosphorylation, suggesting that transactivated EGF receptor is not responsible for this signaling event. Because Gab1 associates with phospholipase C (PLC)
J. Biol. Chem, 10.1074/jbc.M200605200
Submitted on January 22, 2002
Revised on April 2, 2002
Accepted on April 8, 2002
Protein kinase C-
and protein kinase C-
are required for Gab2-associated binder-1 tyrosine-phosphorylation in response to platelet-derived growth factor
, we studied the role of PLC pathway in Gab1 tyrosine-phosphorylation. Gab1 tyrosine-phosphorylation by PDGF was impaired in Chinese hamster ovary (CHO) cells expressing mutant PDGF
receptor (Y977/989F: lacking the binding site for PLC). Pretreatment of VSMC with U73122 (specific PLC inhibitor) inhibited Gab1 tyrosine-phosphorylation as well, indicating the importance of PLC pathway. Gab1 was tyrosine-phosphorylated by phorbol ester to the same extent as PDGF stimulation. Studies using antisense PKC oligonucleotides and specific inhibitors showed that PKC-
and PKC-
are required for Gab1 tyrosine-phosphorylation. Binding of Gab1 to the protein-tyrosine phosphatase SHP2 and phosphatidyl inositol 3-kinase was significantly decreased by PLC and/or PKC inhibition, suggesting the importance of the PLC/PKC dependent Gab1 tyrosine-phosphorylation for the interaction with other signaling molecules. Since PDGF-mediated ERK activation is enhanced in CHO cells that overexpress Gab1, Gab1 serves as an important link between PKC and ERK activation by PDGF receptors in VSMC.
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