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Molecular and Cellular Biology, April 2002, p. 2099-2110, Vol. 22, No. 7
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.7.2099-2110.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Convergence of Multiple Signaling Cascades at Glycogen Synthase Kinase 3: Edg Receptor-Mediated Phosphorylation and Inactivation by Lysophosphatidic Acid through a Protein Kinase C-Dependent Intracellular Pathway

Xianjun Fang,1 Shuangxing Yu,1 Janos L. Tanyi,1 Yiling Lu,1 James R. Woodgett,2 and Gordon B. Mills1*

Department of Molecular Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 ,1 Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada2

Received 26 June 2001/ Returned for modification 18 August 2001/ Accepted 18 December 2001

Lysophosphatidic acid (LPA) is a natural phospholipid with multiple biological functions. We show here that LPA induces phosphorylation and inactivation of glycogen synthase kinase 3 (GSK-3), a multifunctional serine/threonine kinase. The effect of LPA can be reconstituted by expression of Edg-4 or Edg-7 in cells lacking LPA responses. Compared to insulin, LPA stimulates only modest phosphatidylinositol 3-kinase (PI3K)-dependent activation of protein kinase B (PKB/Akt) that does not correlate with the magnitude of GSK-3 phosphorylation induced by LPA. PI3K inhibitors block insulin- but not LPA-induced GSK-3 phosphorylation. In contrast, the effect of LPA, but not that of insulin or platelet-derived growth factor (PDGF), is sensitive to protein kinase C (PKC) inhibitors. Downregulation of endogenous PKC activity selectively reduces LPA-mediated GSK-3 phosphorylation. Furthermore, several PKC isotypes phosphorylate GSK-3 in vitro and in vivo. To confirm a specific role for PKC in regulation of GSK-3, we further studied signaling properties of PDGF receptor ß subunit (PDGFRß) in HEK293 cells lacking endogenous PDGF receptors. In clones expressing a PDGFRß mutant wherein the residues that couple to PI3K and other signaling functions are mutated with the link to phospholipase C{gamma} (PLC{gamma}) left intact, PDGF is fully capable of stimulating GSK-3 phosphorylation. The process is sensitive to PKC inhibitors in contrast to the response through the wild-type PDGFRß. Therefore, growth factors, such as PDGF, which control GSK-3 mainly through the PI3K-PKB/Akt module, possess the ability to regulate GSK-3 through an alternative, redundant PLC{gamma}-PKC pathway. LPA and potentially other natural ligands primarily utilize a PKC-dependent pathway to modulate GSK-3.

* Corresponding author. Mailing address: M. D. Anderson Cancer Center, Department of Molecular Therapeutics, Box 317, 1515 Holcombe Blvd., Houston, TX 77030. Phone: (713) 745-2079. Fax: (713) 745-1184. E-mail: gmills{at}notes.mdacc.tmc.edu.

Molecular and Cellular Biology, April 2002, p. 2099-2110, Vol. 22, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.7.2099-2110.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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