Negative Regulation of Platelet Clearance and of the Macrophage Phagocytic Response by the Transmembrane Glycoprotein SHPS-1

• Published in: The Journal of biological chemistry 2002-10, Vol.277 (42), p.39833-39839
• Main Authors: Yamao, Takuji, Noguchi, Tetsuya, Takeuchi, Osamu, Nishiyama, Uichi, Morita, Haruhiko, Hagiwara, Tetsuya, Akahori, Hironori, Kato, Takashi, Inagaki, Kenjiro, Okazawa, Hideki, Hayashi, Yoshitake, Matozaki, Takashi, Takeda, Kiyoshi, Akira, Shizuo, Kasuga, Masato
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - biosynthesis; Antigens, Differentiation; Biotinylation; Blood Platelets - metabolism; Brain - metabolism; Carrier Proteins - biosynthesis; CD47 Antigen; Cell Membrane - metabolism; Cytoplasm - metabolism; Down-Regulation; Erythrocytes - metabolism; Female; Gene Expression Regulation, Enzymologic; Homozygote; Immunoblotting; Macrophages - metabolism; Male; Megakaryocytes - metabolism; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - metabolism; Mice; Mice, Mutant Strains; Mutation; Neural Cell Adhesion Molecule L1 - chemistry; Neural Cell Adhesion Molecule L1 - metabolism; Phagocytosis; Plasmids - metabolism; Ploidies; Precipitin Tests; Receptors, Immunologic; Signal Transduction; Spleen - metabolism; Spleen - pathology; Stem Cells; Thrombocytopenia; Time Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M203287200

SHPS-1 is a receptor-type glycoprotein that binds and activates the protein-tyrosine phosphatases SHP-1 and SHP-2, and thereby negatively modulates intracellular signaling initiated by various cell surface receptors coupled to tyrosine kinases. SHPS-1 also regulates intercellular communication in the neural and immune systems through its association with CD47 (integrin-associated protein) on adjacent cells. Furthermore, recent studies with fibroblasts derived from mice expressing an SHPS-1 mutant that lacks most of the cytoplasmic region suggested that the intact protein contributes to cytoskeletal function. Mice homozygous for this SHPS-1 mutation have now been shown to manifest thrombocytopenia. These animals did not exhibit a defect in megakaryocytopoiesis or in platelet production. However, platelets were cleared from the bloodstream more rapidly in the mutant mice than in wild-type animals. Furthermore, peritoneal macrophages from the mutant mice phagocytosed red blood cells more effectively than did those from wild-type mice; in addition, they exhibited an increase both in the rate of cell spreading and in the formation of filopodia-like structures at the cell periphery. These results indicate that SHPS-1 both contributes to the survival of circulating platelets and down-regulates the macrophage phagocytic response.