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J. Biol. Chem., Vol. 283, Issue 9, 5249-5257, February 29, 2008

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Different Mechanisms Regulate Lysophosphatidic Acid (LPA)-dependent Versus Phorbol Ester-dependent Internalization of the LPA₁ Receptor^*

Nikhil M. Urs, Andrew P. Kowalczyk, and Harish Radhakrishna¹

From the School of Biology, Georgia Institute of Technology, Atlanta, Georgia 30332 and the Department of Cell Biology, Emory University, Atlanta, Georgia 30322

Lysophosphatidic acid (LPA) stimulates cells by activation of five G-protein-coupled receptors, termed LPA_1–5. The LPA₁ receptor is the most widely expressed and is a major regulator of cell migration. In this study, we show that phorbol ester (PMA)-induced internalization of the LPA₁ receptor requires clathrin AP-2 complexes, protein kinase C, and a distal dileucine motif (amino acids 352 and 353) in the cytoplasmic tail but not β-arrestin. Agonist-dependent internalization of LPA₁, however, requires a cluster of serine residues (amino acids 341–347) located proximal to the dileucine motif, β-arrestin, and to a lesser extent clathrin AP-2. The serine cluster of LPA₁ is required for β-arrestin2-GFP translocation to the plasma membrane and signal desensitization. In contrast, the dileucine motif (IL) is required for both basal and PMA-induced internalization. Evidence for the β-arrestin independence of PMA-induced internalization of LPA₁ comes from the observations that β-arrestin2-GFP is not recruited to the plasma membrane upon PMA treatment and that LPA₁ is readily internalized in β-arrestin1/2 knock-out mouse embryonic fibroblasts. These results indicate that distinct molecular mechanisms regulate agonist-dependent and PMA-dependent internalization of the LPA₁ receptor.

Received for publication, December 7, 2007

^* This work was supported by National Institutes of Health Grants HL 67314 (to H. R.) and AR 050501 (to A. P. K.). 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.

¹ To whom correspondence should be addressed: The Coca-Cola Co., One Coca-Cola Plaza, TEC-437, Atlanta, GA 30301. Tel.: 404-676-4801; Fax: 404-515-5112; E-mail: hradha{at}earthlink.net.

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