Trk receptors use redundant signal transduction pathways involving SHC and PLC-γ1 to mediate NGF responses

Robert M. Stephens, David M. Loeb, Terry D. Copeland, Tony Pawson, Lloyd A. Greene, David R. Kaplan

Research output: Contribution to journalArticle

450 Scopus citations

Abstract

In response to NGF, the Trk receptor tyrosine kinase forms a complex with SHC, a protein that couples receptor tyrosine kinases to p21ras. 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 substrates in NGF signaling, Trk receptors with mutations in Y490 and Y785 (the PLC-γ1 association site) were introduced into PC12nnr5 cells. NGF treatment of PC12nnr5 cells expressing Trk with mutations in either substrate-binding site resulted in normal neurite outgrowth and Erk1 activity and tyrosine phosphorylation. However, PC12nnr5 cells expressing Trk with mutations at both sites failed to stably extend neurites and efficiently induce Erkt activity and tyrosine phosphorylation in response to NGF. We postulate that Trk receptors can activate Erk1 by either SHC- or PLC-γ1-dependent signaling pathways. These results suggest a model whereby Trk receptors utilize at least partially redundant signal transduction pathways to mediate NGF responses.

Original languageEnglish (US)
Pages (from-to)691-705
Number of pages15
JournalNeuron
Volume12
Issue number3
DOIs
StatePublished - Mar 1994
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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