The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA - A model for discriminating proliferation and differentiation

We have isolated a human cDNA for the signaling adapter molecule FRS-2/suc1 -associated neurotrophic factor target and shown that it is tyrosine-phosph orylated in response to nerve growth factor (NGF) stimulation. Importantly, we demonstrate that the phosphotyrosine binding domain of FRS-2 directly b inds the Trk receptors at the same phosphotyrosine residue that binds the s ignaling adapter Shc, suggesting a model in which competitive binding betwe en FRS-2 and Shc regulates differentiation versus proliferation. Consistent with this model, FRS-S binds Grb-2, Crk, the SH2 domain containing tyrosin e phosphatase SH-PTP-S, the cyclin-dependent kinase substrate p13(suc1), an d the Src homology 3 (SH3) domain of Src, providing a functional link betwe en TrkA, cell cycle, and multiple NGF signaling effectors. Importantly, ove rexpression 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.