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J. Biol. Chem., Vol. 282, Issue 33, 24219-24230, August 17, 2007

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Dual Regulation of SIRP Phosphorylation by Integrins and CD47^*

From the Program in Microbial Pathogenesis and Host Defense, Genentech Hall, University of California, San Francisco, California 94158

Signal regulatory protein (SIRP, 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 SIRP, 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 SIRP 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 SIRP phosphorylation in myeloid cells, whereas it is required in endothelial cells. In contrast, integrin-mediated adhesion is required for SIRP phosphorylation in both cell types. This shows that SIRP phosphorylation is dually regulated and demonstrates a new mechanism for functional cooperation between integrins and the integrin-associated protein CD47.

Received for publication, February 22, 2007 , and in revised form, June 19, 2007.

M. J. dedicates this paper to her beloved B. and S. J. who are greatly missed.

^* This work was supported by National Institutes of Health Grants RO1 GM38330 and P01 AI53194. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–5.

¹ To whom correspondence should be addressed: Genentech, Inc., 1 DNA Way, MS33, South San Francisco, CA 94080. Tel.: 650-467-8330; Fax: 650-225-6103; E-mail: brown.eric{at}gene.com.

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