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Originally published In Press as doi:10.1074/jbc.M001862200 on March 28, 2000

J. Biol. Chem., Vol. 275, Issue 24, 18225-18233, June 16, 2000
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Direct Binding of the Signaling Adapter Protein Grb2 to the Activation Loop Tyrosines on the Nerve Growth Factor Receptor Tyrosine Kinase, TrkA*

James I. S. MacDonaldDagger , Ela A. GryzDagger §, Chris J. KubuDagger , Joseph M. VerdiDagger §||, and Susan O. MeakinDagger §**Dagger Dagger

From the Dagger  John P. Robarts Research Institute, Neurodegeneration Group, 100 Perth Drive, London, Ontario N6A 5K8, the § Graduate Program in Neuroscience, the || Department of Physiology, and the ** Department of Biochemistry, the University of Western Ontario, London, Ontario N6A 5C1, Canada

We demonstrate that the signaling adapter, Grb2, binds directly to the neurotrophin receptor tyrosine kinase, TrkA. Grb2 binding to TrkA is independent of Shc, FRS-2, phospholipase Cgamma -1, rAPS, and SH2B and is observed in in vitro binding assays, yeast two-hybrid assays, and in co-immunoprecipitation assays. Grb2 binding to TrkA is mediated by the central SH2 domain, requires a kinase-active TrkA, and is phosphotyrosine-dependent. By analyzing a series of rat TrkA mutants, we demonstrate that Grb2 binds to the carboxyl-terminal residue, Tyr794, as well as to the activation loop tyrosines, Tyr683 and Tyr684. By using acidic amino acid substitutions of the activation loop tyrosines on TrkA, we can stimulate constitutive kinase activity and TrkA-Shc interactions but, importantly, abolish TrkA/Grb2 binding. Thus, in addition to providing the first evidence of direct Grb2 binding to the neurotrophin receptor, TrkA, these data provide the first direct evidence that the activation loop tyrosines of a receptor tyrosine kinase, in addition to their essential role in kinase activation, also serve a direct role in the recruitment of intracellular signaling molecules.

* This work was supported in part by funds from the Medical Research Council of Canada and The Cancer Research Society (to S. O. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a studentship from the Cancer Research Society.

Dagger Dagger To whom correspondence should be addressed: The John P. Robarts Research Institute, Neurodegeneration Group, 100 Perth Drive, London, Ontario N6A 5K8, Canada. Tel.: 519-663-5777, ext. 134304; Fax: 519-663-3789; E-mail: smeakin@rri.on.ca.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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