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J Biol Chem, Vol. 274, Issue 14, 9861-9870, April 2, 1999

The Signaling Adapter FRS-2 Competes with Shc for Binding to the Nerve Growth Factor Receptor TrkA
A MODEL FOR DISCRIMINATING PROLIFERATION AND DIFFERENTIATION

Susan O. Meakin^§¶, James I. S. MacDonald, Ela A. Gryz^§, Christopher J. Kubu, and Joseph M. Verdi^¶

From the  Neurodegeneration Research Group, The John P. Robarts Research Institute, London, Ontario N6A 5K8, Canada and the ^§ Department of Biochemistry, the ^¶ Graduate Program in Neuroscience, and the  Department of Physiology, University of Western Ontario, London, Ontario N6A 5C1, Canada

We have isolated a human cDNA for the signaling adapter molecule FRS-2/suc1-associated neurotrophic factor target and shown that it is tyrosine-phosphorylated in response to nerve growth factor (NGF) stimulation. Importantly, we demonstrate that the phosphotyrosine binding domain of FRS-2 directly binds the Trk receptors at the same phosphotyrosine residue that binds the signaling adapter Shc, suggesting a model in which competitive binding between FRS-2 and Shc regulates differentiation versus proliferation. Consistent with this model, FRS-2 binds Grb-2, Crk, the SH2 domain containing tyrosine phosphatase SH-PTP-2, the cyclin-dependent kinase substrate p13^suc1, and the Src homology 3 (SH3) domain of Src, providing a functional link between TrkA, cell cycle, and multiple NGF signaling effectors. Importantly, overexpression of FRS-2 in cells expressing an NGF nonresponsive TrkA receptor mutant reconstitutes the ability of NGF to stop cell cycle progression and to stimulate neuronal differentiation.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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