TRK RECEPTORS USE REDUNDANT SIGNAL-TRANSDUCTION PATHWAYS INVOLVING SHC AND PLC-GAMMA-1 TO MEDIATE NGF RESPONSES

In response to NCF, the Trk receptor tyrosine kinase forms a complex w ith SHC, a protein that couples receptor tyrosine kinases to p21(ras). Complex formation between Trk and SHC, SHC tyrosine phosphorylation, and association of SHC with Grb2 were mediated by autophosphorylation at Y490 in Trk (NPQYFSD). To determine the role of SHC and other Trk s ubstrates in NGF signaling, Trk receptors with mutations in Y490 and Y 785 (the PLC-gamma 1 association site) were introduced into PC12nnr5 c ells. NGF treatment of PC12nnr5 cells expressing Trk with mutations in either substrate-binding site resulted in normal neurite outgrowth an d Erk1 activity and tyrosine phosphorylation. However, PC12nnr5 cells expressing Trk with mutations at both sites failed to stably extend ne urites and efficiently induce Erk1 activity and tyrosine phosphorylati on in response to NGF. We postulate that Trk receptors can activate Er k1 by either SHC- or PLC-gamma 1-dependent signaling pathways. These r esults suggest a model whereby Trk receptors utilize at least partiall y redundant signal transduction pathways to mediate NGF responses.