Abstract
Growth factor receptor-binding protein 2 (Grb2) acts as an adaptor during signaling from growth factor receptors or the oncogene Bcr/Abl. Grb2 has one SRC homology 2 (SH2) domain (which binds specific phosphotyrosines) and two SH3 domains (which bind proline-rich sequences). Li et al . show that Grb2 is tyrosine phosphorylated when coexpressed with the tyrosine kinase Bcr/Abl or upon stimulation of the epidermal growth factor (EGF) receptor. Although several residues appear to be phosphorylated. Phosphorylation of Y 209 appeared especially important for regulating the interaction of Grb2 with the guanine nucleotide releasing factor Sos, which interacts with the SH3 domains of Grb2. Y 209 is within the COOH-terminal SH3 domain. Analysis of downstream signaling in cells expressing wild-type or the Y209F mutant of Grb2 demonstrated that phosphorylation of Y 209 limits signal duration and extent of Ras activation, activation of the mitogen-activated protein kinases (MAPKs) p44 and p42, and activation of Jun-NH 2 terminal kinase (JNK). Thus, tyrosine phosphorylation of Grb2 appears to be a negative feedback mechanism, allowing cells to produce a transient response to growth factor stimulation. S. Li, A. D. Couvillon, B. B. Brasher, R. A. Van Etten, Tyrosine phosphorylation of Grb2 by Bcr/Abl and epidermal growth factor receptor: A novel regulatory mechanism for tyrosine kinase signaling. EMBO J. 23 : 6793-6804 (2001). [Abstract] [Full Text]
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