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J Biol Chem, Vol. 275, Issue 19, 14573-14578, May 12, 2000

Gelsolin Binding and Cellular Presentation of Lysophosphatidic Acid*

Edward J. GoetzlDagger , Hsinyu Lee, Toshifumi Azuma§, Thomas P. Stossel§, Christoph W. Turck, and Joel S. Karliner

From the Departments of Medicine and Microbiology-Immunology and  Veterans Affairs Medical Center, University of California, San Francisco, California 94143-0711 and § Department of Medicine, Hematology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Lysophosphatidic acid (LPA) in biological fluids binds to serum albumin and other proteins that enhance its effects on cellular functions. The actin-severing protein gelsolin binds LPA with an affinity (Kd = 6 nM) similar to that of the G protein-coupled LPA receptors encoded by endothelial differentiation genes 2, 4, and 7 (Edg-2, -4, and -7 receptors) and greater than that of serum albumin (Kd = 360 nM). At concentrations of 10% or less of that in plasma, which are observed in fluids of injured tissues, purified and recombinant gelsolin augment LPA stimulation of nuclear signals and protein synthesis in rat cardiac myocytes (RCMs) that express Edg-2 and -4 receptors. At concentrations of 20% or more of that in plasma, gelsolin suppresses LPA stimulation of RCMs. The lack of effect of gelsolin on RCM responses to monoclonal anti-Edg-4 receptor antibody plus a phorbol ester without LPA attests to its specificity for LPA delivery and the absence of post-receptor effects. Inhibition of gelsolin binding and cellular delivery of LPA by L-alpha -phosphatidylinositol-4,5-bisphosphate (PIP2) and peptides constituting the two PIP2 binding domains of gelsolin suggests competition between LPA and PIP2 for the same sites. Thus, delivery of LPA to RCMs is affinity-coupled to Edg receptors by gelsolin in a PIP2-regulated process.


* This work was supported in part by National Institutes of Health Grants HL31809 (to E. J. G.) and HL54253 (to T. P. S.) and a Merit Review grant from the Department of Veterans Affairs Research Service (to J. S. K.). These data were presented in part at the 1999 annual meeting of the American Society for Biochemistry and Molecular Biology (41).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: University of California, UB8B, Box 0711, 533 Parnassus, San Francisco, CA 94143-0711. Tel.: 415-476-5339; Fax: 415-476-6915; E-mail: egoetzl@itsa.ucsf.edu.


Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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