SIRPβ1 is expressed as a disulfide-linked homodimer in leukocytes and positively regulates neutrophil transepithelial migration

被引:40
作者
Liu, Y
Soto, I
Tong, Q
Chin, A
Bühring, HJ
Wu, T
Zen, K
Parkos, CA
机构
[1] Georgia State Univ, Dept Biol, Atlanta, GA 30302 USA
[2] Emory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USA
[3] Univ Tubingen, Dept Internal Med 2, Div Hematol Immunol & Oncol, Tubingen, Germany
关键词
D O I
10.1074/jbc.M506419200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (beta) or inhibitory (alpha) isoforms. We reported previously that human neutrophils ( polymorphonuclear leukocytes (PMN)) express multiple SIRP isoforms and that SIRP alpha binding to its ligand CD47 regulates PMN transmigration. Here we further characterized the expression of PMN SIRPs, and we reported that the major SIRP alpha and SIRP beta isoforms expressed in PMN include Bit/PTPNS-1 and SIRP beta 1, respectively. Furthermore, although SIRP alpha (Bit/PTPNS-1) is expressed as a monomer, we showed that SIRP beta 1 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 SIRP beta 1 within the plasma membrane fractions of PMN. In contrast, the majority of SIRP alpha(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 SIRP beta 1 enhanced formylmethionylleucylphenylalanine-driven PMN transepithelial migration. Co-immunoprecipitation experiments to identify associated adaptor proteins revealed a 10-12-kDa protein associated with SIRP beta 1 that was tyrosine-phosphorylated after PMN stimulation and is not DAP10/12 or Fc receptor gamma 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.
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收藏
页码:36132 / 36140
页数:9
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