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J. Biol. Chem., Vol. 279, Issue 46, 47871-47880, November 12, 2004

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Optimal Lysophosphatidic Acid-induced DNA Synthesis and Cell Migration but Not Survival Require Intact Autophosphorylation Sites of the Epidermal Growth Factor Receptor^*

Wenlin Deng, Helen Poppleton¶, Satoshi Yasuda, Natalia Makarova, Yoriko Shinozuka||, De-an Wang, Leonard R. Johnson, Tarun B. Patel**, and Gabor Tigyi

From the Departments of Physiology and Pharmacology, The University of Tennessee Health Science Center, Memphis, Tennessee 38163, and ^||Department of Biology, Ochanomizu University, 2-1-1 Ohtsuka, Bunkyo-ku, Tokyo 112-8610, Japan

Lysophosphatidic acid (LPA)-elicited transphosphorylation of receptor tyrosine kinases has been implicated in mediating extracellular signal-regulated kinase (ERK) 1/2 activation, which is necessary for LPA-induced cell proliferation, migration, and survival. B82L cells lack epidermal growth factor receptor (EGFR) but express LPA_1–3, platelet-derived growth factor (PDGF), ErbB2, and insulin-like growth factor receptor transcripts, yet LPA caused no detectable transphosphorylation of these receptor tyrosine kinases. LPA equally protected B82L cells, or transfectants expressing EGFR, the kinase dead EGFR^K721A, EGFR^Y5F receptor mutant, which lacks five autophosphorylation sites, or EGFR^Y845F, which lacks the Src phosphorylation site from tumor necrosis factor--induced apoptosis. In contrast, LPA-elicited DNA synthesis and migration were augmented in cells expressing EGFR, EGFR^K721A, or EGFR^Y845F, but not EGFR^Y5F, although the PDGF responses were indistinguishable. LPA-induced transphosphorylation of the EGFR, ErbB2, or PDGF receptor was not required for its antiapoptotic effect. EGFR with or without intrinsic kinase activity or without the Src-phosphorylation site augmented, but was not required for, LPA-elicited cell proliferation or migration. In B82L cells, augmentation of these two LPA responses required intact autophosphorylation sites because among the four EGFR mutants, only cells expressing the EGFR^Y5F mutant showed no enhancement. In EGFR^Y5F-expressing cells, LPA failed to elicit tyrosine phosphorylation of Src homologous and collagen protein (SHC) and caused only a modest increase in ERK1/2 phosphorylation similar to that in wild-type B82L cells. The present data pinpoint the lack of importance of the intrinsic kinase activity in contrast to the importance of autophosphorylation sites of the EGFR for SHC phosphorylation in the enhancement of select ERK1/2-dependent LPA responses.

Received for publication, May 17, 2004 , and in revised form, September 7, 2004.

^* This work was supported in part by United States Public Health Service Grants DK16505 (to L. R. J.), HL48308 (to T. B. P.), HL59679 (to T. B. P.), HL61469 (to G. T.), and CA92160 (to G. T.). 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.

^¶ Present address: Dept. of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38109.

^** Present address: Dept. of Pharmacology, Loyola University Chicago, Stritch School of Medicine, 2160 First South Avenue, Maywood, IL 60153.

To whom correspondence should be addressed: 894 Union Ave., Memphis, TN 38163, Tel.: 901-448-4793; Fax: 901-448-7126; E-mail: gtigyi{at}physio1.utmem.edu.

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