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Molecular and Cellular Biology, May 2001, p. 2981-2990, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.2981-2990.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Phosphorylation of Nuclear Phospholipase C beta 1 by Extracellular Signal-Regulated Kinase Mediates the Mitogenic Action of Insulin-Like Growth Factor I

Aimin Xu,1 Pann-Ghill Suh,2 Nelly Marmy-Conus,3 Richard B. Pearson,3 Oh Yong Seok,2 Lucio Cocco,4 and R. Stewart Gilmour1,*

Liggins Institute, School of Medicine, University of Auckland, Auckland, New Zealand1; Division of Molecular Life Sciences, Department of Life Science, Pohang University of Science and Technology, Pohang, South Korea2; Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne, Australia3; and Cellular Signalling Laboratory, Department of Anatomical Sciences, University of Bologna, Bologna, Italy4

Received 29 November 2000/Returned for modification 29 December 2000/Accepted 5 February 2001

It is well established that a phosphoinositide (PI) cycle which is operationally distinct from the classical plasma membrane PI cycle exists within the nucleus, where it is involved in both cell proliferation and differentiation. However, little is known about the regulation of the nuclear PI cycle. Here, we report that nucleus-localized phospholipase C (PLC) beta 1, the key enzyme for the initiation of this cycle, is a physiological target of extracellular signal-regulated kinase (ERK). Stimulation of Swiss 3T3 cells with insulin-like growth factor I (IGF-I) caused rapid nuclear translocation of activated ERK and concurrently induced phosphorylation of nuclear PLC beta 1, which was completely blocked by the MEK inhibitor PD 98059. Coimmunoprecipitation detected a specific association between the activated ERK and PLC beta 1 within the nucleus. In vitro studies revealed that recombinant PLC beta 1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by PKA. The ERK phosphorylation site was mapped to serine 982, which lies within a PSSP motif located in the characteristic carboxy-terminal tail of PLC beta 1. In cells overexpressing a PLC beta 1 mutant in which serine 982 is replaced by glycine (S982G), IGF-I failed to activate the nuclear PI cycle, and its mitogenic effect was also markedly attenuated. Expression of S982G was found to inhibit ERK-mediated phosphorylation of endogenous PLC beta 1. This result suggests that ERK-evoked phosphorylation of PLC beta 1 at serine 982 plays a critical role in the activation of the nuclear PI cycle and is also crucial to the mitogenic action of IGF-I.

* Corresponding author. Mailing address: Liggins Institute, School of Medicine, University of Auckland, Private Bag 92019, 85 Park Rd., Auckland, New Zealand. Phone: 64 9 373 7599, ext. 4489. Fax: 64 9 373 7492. E-mail: s.gilmour{at}auckland.ac.nz.

Molecular and Cellular Biology, May 2001, p. 2981-2990, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.2981-2990.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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