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

doi:10.1128/MCB.21.9.2981-2990.2001

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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 membranePI cycle exists within the nucleus, where it is involved in bothcell proliferation and differentiation. However, little is knownabout the regulation of the nuclear PI cycle. Here, we reportthat nucleus-localized phospholipase C (PLC) $beta$ 1, the key enzymefor the initiation of this cycle, is a physiological target ofextracellular signal-regulated kinase (ERK). Stimulation of Swiss3T3 cells with insulin-like growth factor I (IGF-I) caused rapidnuclear translocation of activated ERK and concurrently inducedphosphorylation of nuclear PLC $beta$ 1, which was completely blockedby the MEK inhibitor PD 98059. Coimmunoprecipitation detecteda specific association between the activated ERK and PLC $beta$ 1 withinthe nucleus. In vitro studies revealed that recombinant PLC $beta$ 1could be efficiently phosphorylated by activated mitogen-activatedprotein kinase but not by PKA. The ERK phosphorylation site wasmapped to serine 982, which lies within a PSSP motif located inthe characteristic carboxy-terminal tail of PLC $beta$ 1. In cells overexpressinga PLC $beta$ 1 mutant in which serine 982 is replaced by glycine (S982G),IGF-I failed to activate the nuclear PI cycle, and its mitogeniceffect was also markedly attenuated. Expression of S982G was foundto inhibit ERK-mediated phosphorylation of endogenous PLC $beta$ 1.This result suggests that ERK-evoked phosphorylation of PLC $beta$ 1at serine 982 plays a critical role in the activation of the nuclearPI 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, 85Park Rd., Auckland, New Zealand. Phone: 64 9 373 7599, ext. 4489.Fax: 64 9 373 7492. E-mail: s.gilmour{at}auckland.ac.nz.

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

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