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

doi:10.1016/0896-6273(94)90223-2

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 journal › Article › peer-review

457 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 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 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 language	English (US)
Pages (from-to)	691-705
Number of pages	15
Journal	Neuron
Volume	12
Issue number	3
DOIs	https://doi.org/10.1016/0896-6273(94)90223-2
State	Published - Mar 1994
Externally published	Yes

ASJC Scopus subject areas

General Neuroscience

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10.1016/0896-6273(94)90223-2

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@article{46b8cd75588f4da296d83099f3bae179,

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

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.",

author = "Stephens, {Robert M.} and Loeb, {David M.} and Copeland, {Terry D.} and Tony Pawson and Greene, {Lloyd A.} and Kaplan, {David R.}",

note = "Funding Information: We thank S. Rabin and A. Maewal for expert technical assistance and D. Morrison, K. Shibuya, and N. Michaud for critical reading of the manuscript. We also thank J. Blenis, S. G. Rhee, S. Soltoff, L. Cantley, J. Winslow, G. Burton, V. Cleghon, N. Michaud, and D. Morrison for generous girls of reagents. This research was sponsored in part by the National Cancer Institute DHHS, under contract no. N01-CO-74101 with ABL, and by grants from the NIH-NINDS and March of Dimes Birth Defects Foundation (L. A. G.).",

year = "1994",

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doi = "10.1016/0896-6273(94)90223-2",

language = "English (US)",

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T1 - Trk receptors use redundant signal transduction pathways involving SHC and PLC-γ1 to mediate NGF responses

AU - Stephens, Robert M.

AU - Loeb, David M.

AU - Copeland, Terry D.

AU - Pawson, Tony

AU - Greene, Lloyd A.

AU - Kaplan, David R.

N1 - Funding Information: We thank S. Rabin and A. Maewal for expert technical assistance and D. Morrison, K. Shibuya, and N. Michaud for critical reading of the manuscript. We also thank J. Blenis, S. G. Rhee, S. Soltoff, L. Cantley, J. Winslow, G. Burton, V. Cleghon, N. Michaud, and D. Morrison for generous girls of reagents. This research was sponsored in part by the National Cancer Institute DHHS, under contract no. N01-CO-74101 with ABL, and by grants from the NIH-NINDS and March of Dimes Birth Defects Foundation (L. A. G.).

PY - 1994/3

Y1 - 1994/3

N2 - 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.

AB - 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.

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JO - Neuron

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ER -

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

Abstract

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