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A more recent version of this article appeared on October 8, 2004
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M407631200v1
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Papers In Press, published online ahead of print July 29, 2004
J. Biol. Chem, 10.1074/jbc.M407631200
Submitted on July 7, 2004
Revised on July 29, 2004
Accepted on July 29, 2004

Mechanism of CD47-induced alpha 4beta 1 integrin activation and adhesion in sickle reticulocytes

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

Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365

Corresponding Author: parise{at}med.unc.edu

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 (SCD). However, the CD47-activated SS RBC adhesion receptor(s) that mediated adhesion to immobilized TSP remained unknown. Here we demonstrate that the alpha 4beta 1 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 alpha 4beta 1 on SS RBCs as indicated by an RGD-dependent interaction of this integrin with soluble, plasma fibronectin. However, CD47 engagement also induces an alpha 4beta 1-mediated, RGD-independent adhesion of SS RBCs to immobilized VCAM-1. CD47 signaling in SS RBCs appears to be independent of large scale changes in cAMP formation, but nonetheless promotes alpha 4beta 1-mediated adhesion via a protein kinase A-dependent, serine phosphorylation of the alpha 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 alpha 4beta 1 from cytoskeletal restraints. In addition, CD47 co-immunoprecipitates with alpha 4beta 1 in a sickle reticulocyte-enriched fraction of SS RBCs. These studies therefore identify the alpha 4beta 1 integrin on SS RBCs as a CD47-activated receptor for TSP, VCAM-1, and plasma fibronectin, and reveal novel binding characteristics of this integrin.


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