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J. Biol. Chem., Vol. 279, Issue 41, 42393-42402, October 8, 2004

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Mechanism of CD47-induced ₄₁ Integrin Activation and Adhesion in Sickle Reticulocytes^*

Julia E. Brittain, Jaewon Han¶, Kenneth I. Ataga||, Eugene P. Orringer||, and Leslie V. Parise**

From the Departments of Pharmacology and ^||Medicine, the ^**Carolina Cardiovascular Biology Center and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365 and the Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037

We recently reported that CD47 (integrin-associated protein) on sickle red blood cells (SS RBCs) activates G-protein-dependent signaling, which promotes cell adhesion to immobilized thrombospondin (TSP) under relevant shear stress. These data suggested that signal transduction in SS RBCs may contribute to the vaso-occlusive pathology observed in sickle cell disease. However, the CD47-activated SS RBC adhesion receptor(s) that mediated adhesion to immobilized TSP remained unknown. Here we demonstrate that the ₄₁ integrin (VLA-4) is the receptor that mediates CD47-stimulated SS RBC adhesion to immobilized TSP. This adhesion requires both the N-terminal heparin-binding domain and the RGD site of TSP. CD47 signaling induces an "inside-out" activation of ₄₁ on SS RBCs as indicated by an RGD-dependent interaction of this integrin with soluble, plasma fibronectin. However, CD47 engagement also induces an ₄₁-mediated, RGD-independent adhesion of SS RBCs to immobilized vascular cell adhesion molecule-1 (VCAM-1). CD47 signaling in SS RBCs appears to be independent of large scale changes in cAMP formation but nonetheless promotes ₄₁-mediated adhesion via a protein kinase A-dependent, serine phosphorylation of the ₄ cytoplasmic domain. CD47-activated SS RBC adhesion absolutely requires the Src family tyrosine kinases and is also enhanced by treatment of SS RBCs with low concentrations of cytochalasin D, which may release ₄₁ from cytoskeletal restraints. In addition, CD47 co-immunoprecipitates with ₄₁ in a sickle reticulocyte-enriched fraction of SS RBCs. These studies therefore identify the ₄₁ integrin on SS RBCs as a CD47-activated receptor for TSP, VCAM-1, and plasma fibronectin, revealing novel binding characteristics of this integrin.

Received for publication, July 7, 2004 , and in revised form, July 29, 2004.

^* This work was supported by National Institutes of Health Grants RO1 HL067440 (to L. V. P.), RR00046 (to E. P. O.), Hematology Post-doctoral Training Grant T32HL07149 (to J. E. B.), and Duke-UNC Comprehensive Sickle Cell Center Grant U54 HL70769. This work was presented in part at the Annual Meeting of the American Society of Hematology, December 2001, Orlando, FL. 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.

^¶ Current address: Dept. of Medicine, University of California, San Diego 92093.

To whom correspondence should be addressed: Dept. of Pharmacology, The University of North Carolina at Chapel Hill, CB 7365, Chapel Hill NC 27599-7365. Tel.: 919-966-2238; Fax: 919-966-5640; E-mail: parise{at}med.unc.edu.

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