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Molecular and Cellular Biology, April 2001, p. 2695-2705, Vol. 21, No. 8
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.8.2695-2705.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Sustained Signaling by Phospholipase C-gamma Mediates Nerve Growth Factor-Triggered Gene Expression

Deog-Young Choi,1,dagger Juan Jose Toledo-Aral,1,Dagger Rosalind Segal,2 and Simon Halegoua1,*

Department of Neurobiology & Behavior, State University of New York at Stony Brook, Stony Brook, New York 11794-5230,1 and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 021152

Received 16 November 2000/Returned for modification 21 December 2000/Accepted 24 January 2001

In contrast to conventional signaling by growth factors that requires their continual presence, a 1-min pulse of nerve growth factor (NGF) is sufficient to induce electrical excitability in PC12 cells due to induction of the peripheral nerve type 1 (PN1) sodium channel gene. We have investigated the mechanism for this triggered signaling pathway by NGF in PC12 cells. Mutation of TrkA at key autophosphorylation sites indicates an essential role for the phospholipase C-gamma (PLC-gamma ) binding site, but not the Shc binding site, for NGF-triggered induction of PN1. In concordance with results with Trk mutants, drug-mediated inhibition of PLC-gamma activity also blocks PN1 induction by NGF. Examination of the kinetics of TrkA autophosphorylation indicates that triggered signaling does not result from sustained activation and autophosphorylation of the TrkA receptor kinase, whose phosphorylation state declines rapidly after NGF removal. Rather, TrkA triggers an unexpectedly prolonged phosphorylation and activation of PLC-gamma signaling that is sustained for up to 2 h. Prevention of the elevation of intracellular Ca2+ levels using BAPTA-AM results in a block of PN1 induction by NGF. Sustained signaling by PLC-gamma provides a means for differential neuronal gene induction after transient exposure to NGF.

* Corresponding author. Mailing address: Department of Neurobiology & Behavior, State University of New York at Stony Brook, Stony Brook, NY 11794-5230. E-mail: simon.halegoua{at}sunysb.edu.

dagger Present address: Life Science Research Institute, LG Chem Research Park, Yousong-gu, Taejon 305-380, Korea.

Dagger Present address: Departamento de Fisiologia Medica y Biofisica, Facultad de Medicina, Universitad de Sevilla, Sevilla 41009, Spain.

Molecular and Cellular Biology, April 2001, p. 2695-2705, Vol. 21, No. 8
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.8.2695-2705.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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