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J. Biol. Chem., Vol. 280, Issue 43, 36132-36140, October 28, 2005

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SIRP1 Is Expressed as a Disulfide-linked Homodimer in Leukocytes and Positively Regulates Neutrophil Transepithelial Migration^*

Yuan Liu1, Ileana Soto, Qiao Tong, Alex Chin, Hans-Jörg Bühring¶, Tao Wu, Ke Zen, and Charles A. Parkos1

From the Department of Biology, Georgia State University, Atlanta, Georgia 30302, Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, and ^¶Division of Hematology, Immunology, and Oncology, Department of Internal Medicine II, University of Tübingen, Tübingen, Germany

Signal regulatory proteins (SIRPs) comprise a family of cell surface signaling receptors differentially expressed in leukocytes and the central nervous system. Although the extracellular domains of SIRPs are highly similar, classical motifs in the cytoplasmic or transmembrane domains distinguish them as either activating () or inhibitory () isoforms. We reported previously that human neutrophils (polymorphonuclear leukocytes (PMN)) express multiple SIRP isoforms and that SIRP binding to its ligand CD47 regulates PMN transmigration. Here we further characterized the expression of PMN SIRPs, and we reported that the major SIRP and SIRP isoforms expressed in PMN include Bit/PTPNS-1 and SIRP1, respectively. Furthermore, although SIRP (Bit/PTPNS-1) is expressed as a monomer, we showed that SIRP1 is expressed on the cell surface as a disulfide-linked homodimer with bond formation mediated by Cys-320 in the membrane-proximal Ig loop. Subcellular fractionation studies revealed a major pool of SIRP1 within the plasma membrane fractions of PMN. In contrast, the majority of SIRP (Bit/PTPNS-1) is present in fractions enriched in secondary granules and is translocated to the cell surface after chemoattractant (formylmethionylleucylphenylalanine) stimulation. Functional studies revealed that antibody-mediated ligation of SIRP1 enhanced formylmethionylleucylphenylalanine-driven PMN transepithelial migration. Co-immunoprecipitation experiments to identify associated adaptor proteins revealed a 10–12-kDa protein associated with SIRP1 that was tyrosine-phosphorylated after PMN stimulation and is not DAP10/12 or Fc receptor chain. These results provide new insights into the structure and function of SIRPs in leukocytes and their potential role(s) in fine-tuning responses to inflammatory stimuli.

Received for publication, June 13, 2005 , and in revised form, July 27, 2005.

^* This work was supported in part by National Institutes of Health Grants DK62894 (to Y. L.), DK72564, HL72124, and DK61379 (to C. A. P.), Digestive Diseases Minicenter Grant DK064399 (tissue culture and antibody core), and a fellowship from the Canadian Association of Gastroenterology, Canadian Institutes of Health Research, and Axcan Pharma Inc. (to A. C.). 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 Table S and Figs. S1–S3.

¹ To whom correspondence may be addressed: Dept. of Biology, Georgia State University, P. O. Box 4010, Atlanta, GA 30303. Tel.: 404-651-0426; Fax: 404-651-2509; E-mail: yliu{at}gsu.edu. ² To whom correspondence may be addressed: Dept. of Pathology, Emory University, Whitehead Biomedical Bldg., Rm. 105B, Atlanta, GA 30322. Tel.: 404-727-8536; Fax: 404-727-3321; E-mail: cparkos{at}emory.edu.

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