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J. Biol. Chem., Vol. 283, Issue 6, 3618-3627, February 8, 2008

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Autophosphorylation Docking Site Tyr-867 in Mer Receptor Tyrosine Kinase Allows for Dissociation of Multiple Signaling Pathways for Phagocytosis of Apoptotic Cells and Down-modulation of Lipopolysaccharide-inducible NF-B Transcriptional Activation^*

Nitu Tibrewal¹, Yi Wu¹², Veera D'mello, Reiko Akakura, Thaddeus C. George, Brian Varnum^¶, and Raymond B. Birge³

From the Department of Biochemistry & Molecular Biology, University of Medicine and Dentistry of New Jersey (UMDNJ)-New Jersey Medical School, Newark New Jersey 07103, Amnis Corporation, Seattle, Washington 98121, and the ^¶Inflammation Department, Amgen Pharmaceuticals, Amgen, Inc., Thousand Oaks, California 91320

Efficient clearance of apoptotic cells is essential for tissue homeostasis, allowing for cellular turnover without inflammatory consequences. The Mer (Nyk and c-Eyk) receptor tyrosine kinase (Mertk) is involved in two aspects of apoptotic cell clearance by acting as a receptor for Gas6, a -carboxylated phosphatidylserine-binding protein that bridges apoptotic and viable cells. First, Mertk acts in a bona fide engulfment pathway in concert with vβ5 integrin by regulating cytoskeletal assemblages, and second, it acts as a negative regulator for inflammation by down-modulating pro-inflammatory signals mediated from bacterial lipopolysaccharide-Toll-like receptor 4 (TLR4) signaling, and hence recapitulating anti-inflammatory immune modulation by apoptotic cells. Here we describe Mertk post-receptor events that govern phagocytosis and cytoskeletal signaling are principally mediated by autophosphorylation site Tyr-867. Using the Mertk Y867F mutant and pharmacological inhibitors, we show that Tyr-867 is required for phosphatidylinositol 3-kinase and phospholipase C2 activation; their activation in turn elicits protein kinase C-dependent signals that act on the actin cytoskeleton. Although Mertk^Y867F blocked the tyrosine phosphorylation of FAK on Tyr-861 and p130^cas and also abrogated the phagocytosis of apoptotic cells, this mutant did not suppress lipopolysaccharide-inducible NF-B transcription, nor was NF-B activation dependent on the protein kinase C inhibitor, calphostin C. Finally, unlike the cytoskeletal events associated with Tyr-867 autophosphorylation, the trans-inhibition of NF-B occurred in a postnuclear-dependent fashion independent of cytosolic IB phosphorylation and p65/RelA sequestration. Taken together, these data suggest that Mertk has distinct and separable effects for phagocytosis and for resolving inflammation, providing a molecular rationale for how immune licensing and inflammation can be dissociated from phagocytosis in a single phagocytic receptor.

Received for publication, August 17, 2007 , and in revised form, November 12, 2007.

^* This work was supported by an Arthritis Foundation grant (to R. B. B.) and from the UMDNJ Research Foundation. 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 Both authors contributed equally to this work.

² Present address: The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, 3400 North Broad St., Philadelphia, Pennsylvania 19140.

³ To whom correspondence should be addressed. Tel.: 973-972-4497; Fax: 973-972-5594; E-mail: birgera{at}umdnj.edu.

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