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J. Biol. Chem., Vol. 278, Issue 41, 39931-39940, October 10, 2003

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Involvement of Phospholipase D2 in Lysophosphatidate-induced Transactivation of Platelet-derived Growth Factor Receptor- in Human Bronchial Epithelial Cells^*

Lixin Wang , Rhett Cummings , Yutong Zhao , Andrius Kazlauskas , James K. S. Sham , Andrew Morris ¶, Steve Georas , David N. Brindley || and Viswanathan Natarajan  **

From the Department of Medicine, Division of Pulmonary and Critical Care, Johns Hopkins University, Baltimore, Maryland 21224, the Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114, the ^¶Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, North Carolina 27599, and the ^||Department of Biochemistry, Signal Transduction Research Group, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

Lysophosphatidate (LPA) mediates multiple cellular responses via heterotrimeric G protein coupled LPA-1, LPA-2, and LPA-3 receptors. Many G protein-coupled receptors stimulate ERK following tyrosine phosphorylation of growth factor receptors; however, the mechanism(s) of transactivation of receptor tyrosine kinases are not well defined. Here, we provide evidence for the involvement of phospholipase D (PLD) in LPA-mediated transactivation of platelet-derived growth factor receptor- (PDGF-R). In primary cultures of human bronchial epithelial cells (HBEpCs), LPA stimulated tyrosine phosphorylation of PDGF-R and threonine/tyrosine phosphorylation of ERK1/2. The LPA-mediated activation of ERK and tyrosine phosphorylation of PDGF-R was attenuated by tyrphostin AG 1296, an inhibitor of PDGF-R kinase, suggesting transactivation of PDGF-R by LPA. Furthermore, LPA-, but not PDGF -chain homodimer-induced tyrosine phosphorylation of PDGF-R was partially blocked by pertussis toxin, indicating coupling of LPA-R(s) to G_i. Exposure of HBEpCs to LPA activated PLD. Butan-1-ol, which acts as an acceptor of phosphatidate generated by the PLD pathway, blocked LPA-mediated transactivation of PDGF-R. This effect was not seen with butan-3-ol, suggesting PLD involvement. The role of PLD1 and PLD2 in the PDGF-R transactivation by LPA was investigated by infection of cells with adenoviral constructs of wild type and catalytically inactive mutants of PLD. LPA activated both PLD1 and PLD2 in HBEpCs; however, infection of cells with cDNA for wild type PLD2, but not PLD1, increased the tyrosine phosphorylation of PDGF-R in response to LPA. Also, the LPA-mediated tyrosine phosphorylation of PDGF-R was attenuated by the catalytically inactive mutant mPLD2-K758R. Infection of HBEpCs with adenoviral constructs of wild type hPLD1, mPLD2, and the inactive mutants of hPLD1 and mPLD2 resulted in association of PLD2 wild type and inactive mutant proteins with the PDGF-R compared with PLD1. These results show for the first time that transactivation of PDGF-R by LPA in HBEpCs is regulated by PLD2.

Received for publication, March 21, 2003 , and in revised form, July 24, 2003.

^* This work was supported by National Institutes of Health Grant HL 71152 (to V. N.) and by Canadian Institutes of Health Research Grant MOP 10504 (to D. N. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Johns Hopkins University School of Medicine, Mason F. Lord Bldg., Rm. 675, 5200 Eastern Ave., Baltimore, MD 21224. Tel.: 410-550-7748; Fax: 410-550-8571; E-mail: vnataraj{at}jhmi.edu.

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