دورية
Direct Binding of the Signaling Adapter Protein Grb2 to the Activation Loop Tyrosines on the Nerve Growth Factor Receptor Tyrosine Kinase, TrkA*
| العنوان: | Direct Binding of the Signaling Adapter Protein Grb2 to the Activation Loop Tyrosines on the Nerve Growth Factor Receptor Tyrosine Kinase, TrkA* |
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| المؤلفون: | MacDonald, James I.S., Gryz, Ela A., Kubu, Chris J., Verdi, Joseph M., Meakin, Susan O. |
| المصدر: | Journal of Biological Chemistry; June 2000, Vol. 275 Issue: 24 p18225-18233, 9p |
| مستخلص: | 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 Cγ-1, rAPS, and SH2B and is observed in in vitrobinding 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, Tyr683and 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. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 00219258 1083351X |
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| DOI: | 10.1074/jbc.M001862200 |