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Mechanism of CD47-induced alpha4beta1 integrin activation and adhesion in sickle reticulocytes.
J Biol Chem. 2004 Oct 08; 279(41):42393-402.JB

Abstract

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 alpha4beta1 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 alpha4beta1 on SS RBCs as indicated by an RGD-dependent interaction of this integrin with soluble, plasma fibronectin. However, CD47 engagement also induces an alpha4beta1-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 alpha4beta1-mediated adhesion via a protein kinase A-dependent, serine phosphorylation of the alpha4 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 alpha4beta1 from cytoskeletal restraints. In addition, CD47 co-immunoprecipitates with alpha4beta1 in a sickle reticulocyte-enriched fraction of SS RBCs. These studies therefore identify the alpha4beta1 integrin on SS RBCs as a CD47-activated receptor for TSP, VCAM-1, and plasma fibronectin, revealing novel binding characteristics of this integrin.

Authors+Show Affiliations

Department of Pharmacology, University of North Carolina at Chapel Hill, 27599-7365, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15292185

Citation

Brittain, Julia E., et al. "Mechanism of CD47-induced Alpha4beta1 Integrin Activation and Adhesion in Sickle Reticulocytes." The Journal of Biological Chemistry, vol. 279, no. 41, 2004, pp. 42393-402.
Brittain JE, Han J, Ataga KI, et al. Mechanism of CD47-induced alpha4beta1 integrin activation and adhesion in sickle reticulocytes. J Biol Chem. 2004;279(41):42393-402.
Brittain, J. E., Han, J., Ataga, K. I., Orringer, E. P., & Parise, L. V. (2004). Mechanism of CD47-induced alpha4beta1 integrin activation and adhesion in sickle reticulocytes. The Journal of Biological Chemistry, 279(41), 42393-402.
Brittain JE, et al. Mechanism of CD47-induced Alpha4beta1 Integrin Activation and Adhesion in Sickle Reticulocytes. J Biol Chem. 2004 Oct 8;279(41):42393-402. PubMed PMID: 15292185.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanism of CD47-induced alpha4beta1 integrin activation and adhesion in sickle reticulocytes. AU - Brittain,Julia E, AU - Han,Jaewon, AU - Ataga,Kenneth I, AU - Orringer,Eugene P, AU - Parise,Leslie V, Y1 - 2004/07/29/ PY - 2004/8/5/pubmed PY - 2004/12/16/medline PY - 2004/8/5/entrez SP - 42393 EP - 402 JF - The Journal of biological chemistry JO - J Biol Chem VL - 279 IS - 41 N2 - 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 alpha4beta1 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 alpha4beta1 on SS RBCs as indicated by an RGD-dependent interaction of this integrin with soluble, plasma fibronectin. However, CD47 engagement also induces an alpha4beta1-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 alpha4beta1-mediated adhesion via a protein kinase A-dependent, serine phosphorylation of the alpha4 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 alpha4beta1 from cytoskeletal restraints. In addition, CD47 co-immunoprecipitates with alpha4beta1 in a sickle reticulocyte-enriched fraction of SS RBCs. These studies therefore identify the alpha4beta1 integrin on SS RBCs as a CD47-activated receptor for TSP, VCAM-1, and plasma fibronectin, revealing novel binding characteristics of this integrin. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/15292185/Mechanism_of_CD47_induced_alpha4beta1_integrin_activation_and_adhesion_in_sickle_reticulocytes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)76980-2 DB - PRIME DP - Unbound Medicine ER -