Editors' ChoiceCell Biology

Negative Feedback

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Science's STKE  11 Dec 2001:
Vol. 2001, Issue 112, pp. tw454
DOI: 10.1126/stke.2001.112.tw454

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 Y209 appeared especially important for regulating the interaction of Grb2 with the guanine nucleotide releasing factor Sos, which interacts with the SH3 domains of Grb2. Y209 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 Y209 limits signal duration and extent of Ras activation, activation of the mitogen-activated protein kinases (MAPKs) p44 and p42, and activation of Jun-NH2 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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