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J. Biol. Chem., Vol. 282, Issue 37, 27392-27401, September 14, 2007

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CD36 Signals to the Actin Cytoskeleton and Regulates Microglial Migration via a p130Cas Complex^*

Lynda M. Stuart, Susan A. Bell^¶, Cameron R. Stewart^¶, Jessica M. Silver^¶, James Richard^¶, Julie L. Goss^¶, Anita A. Tseng^¶, Ailiang Zhang, Joseph B. El Khoury^||, and Kathryn J. Moore^¶1

From the Developmental Immunology/Department of Pediatrics, the ^¶Lipid Metabolism Unit, and ^||Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and University of Edinburgh Centre for Inflammation Research, Edinburgh EH16 4TJ, United Kingdom

The pattern recognition receptor CD36 initiates a signaling cascade that promotes microglial activation and recruitment to -amyloid deposits in the brain. In the present study we identify the focal adhesion-associated proteins p130Cas, Pyk2, and paxillin as novel members of the tyrosine kinase signaling pathway downstream of CD36 and show that assembly of this complex is essential for microglial migration. In primary microglia and macrophages exposed to -amyloid, the scaffolding protein p130Cas is rapidly tyrosine-phosphorylated and co-localizes with CD36 to membrane ruffles contemporaneous with F-actin polymerization. These -amyloid-stimulated events are not detected in CD36 null cells and are dependent on CD36 activation of Src family tyrosine kinases. Fyn, a Src kinase known to interact with CD36, co-precipitates with p130Cas and is an essential upstream intermediate in the signaling pathways leading to phosphorylation of the p130Cas substrate domain. Furthermore, the p130Cas-interacting kinase Pyk2 and the cytoskeletal adapter protein paxillin also demonstrate CD36-dependent phosphorylation, identifying these focal adhesion molecules as additional members of this -amyloid signaling cascade. Disruption of this p130Cas complex by small interfering RNA silencing inhibits p44/42 mitogen-activated protein kinase phosphorylation and microglial migration, illustrating the importance of this pathway in microglial activation and recruitment. Together, these data are the first to identify the signaling cascade that directly links CD36 to the actin cytoskeleton and, thus, implicates it in diverse processes such as cellular migration, adhesion, and phagocytosis.

Received for publication, April 4, 2007 , and in revised form, July 2, 2007.

^* This work was supported by National Institutes of Health Grant R01AG20255 (to K. J. M.), the Ellison Medical Foundation (to K. J. M.), and Wellcome Trust Clinician Scientist Grant 068089/Z/02/Z (to L. M. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S4C.

¹ To whom correspondence should be addressed: Lipid Metabolism Unit, Massachusetts General Hospital, 55 Fruit St., GRJ1308, Boston, MA 02114. Tel.: 617-726-0511; Fax: 617-726-2879; E-mail: kmoore{at}molbio.mgh.harvard.edu.

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