Dual regulation of SIRP α phosphorylation by integrins and CD47

Abstract

Signal regulatory protein α (SIRPα, SHPS-1) is a plasma membrane receptor for CD47 and a key regulator of phagocytosis, growth factor signaling, and migration. Phosphorylation of immunoreceptor tyrosine-based inhibition motifs in its cytoplasmic tail is essential for the functional effects of SIRPα, at least in part, because the phosphorylated immunoreceptor tyrosine-based inhibition motifs recruit Src homology 2 domain-containing tyrosine phosphatases. Ligation by CD47 and integrin engagement both have been thought to regulate SIRPα phosphorylation. However, their distinct contributions have not been distinguished. Here, we show that the importance of CD47 varies with cell type, since ligation of CD47 is not necessary for SIRPα phosphorylation in myeloid cells, whereas it is required in endothelial cells. In contrast, integrin-mediated adhesion is required for SIRPα phosphorylation in both cell types. This shows that SIRPα phosphorylation is dually regulated and demonstrates a new mechanism for functional cooperation between integrins and the integrin-associated protein CD47. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.