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A more recent version of this article appeared on June 9, 2000
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M001862200v1
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Papers In Press, published online ahead of print March 28, 2000
J. Biol. Chem, 10.1074/jbc.M001862200
Submitted on March 6, 2000
Accepted on March 28, 2000

2Direct Binding of the Signaling Adapter Protein Grb2 to the Activation Loop Tyrosines on the Nerve Growth Factor Receptor Tyrosine Kinase, TrkA

James I.S. MacDonald, Ela A. Gryz, Chris J. Kubu, Joseph M. Verdi, and Susan O. Meakin

Neurodegeneration Group, The John P. Robarts Research Institute, London, Ontario N6A 5K8

Corresponding Author: smeakin{at}rri.on.ca

We demonstrate that the signaling adapter, Grb2, binds directly to the neurotrophin receptor tyrosine kinase (RTK), TrkA. Grb2 binding to TrkA is independent of Shc, FRS-2, PLCgamma -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 carboxy-terminal residue, Yer794, as well as to the activation loop tyrosines, Yer683Yer684. 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 an RTK, in addition to their essential role in kinase activation, also serve a direct role in the recruitment of intracellular signaling molecules.


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