Negative regulation of platelet clearance and of the macrophage phagocytic response by the transmembrane glycoprotein SHPS-1.
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.
Yamao
Takuji
T
Division of Diabetes, Digestive, and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Noguchi
Tetsuya
T
Takeuchi
Osamu
O
Nishiyama
Uichi
U
Morita
Haruhiko
H
Hagiwara
Tetsuya
T
Akahori
Hironori
H
Kato
Takashi
T
Inagaki
Kenjiro
K
Okazawa
Hideki
H
Hayashi
Yoshitake
Y
Matozaki
Takashi
T
Takeda
Kiyoshi
K
Akira
Shizuo
S
Kasuga
Masato
M
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000943:Antigens, Differentiation; D019921:Biotinylation; D001792:Blood Platelets / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000096:biosynthesis; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006720:Homozygote; D015151:Immunoblotting; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D039842:Neural Cell Adhesion Molecule L1 / Q000737:chemistry* / Q000378:metabolism; D010587:Phagocytosis; D010957:Plasmids / Q000378:metabolism; D011003:Ploidies; D011233:Precipitin Tests; D011971:Receptors, Immunologic; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells; D013921:Thrombocytopenia; D013997:Time Factors
D015703:Antigens, CD; D000943:Antigens, Differentiation; D051928:CD47 Antigen; D002352:Carrier Proteins; C497895:Cd47 protein, mouse; D008562:Membrane Glycoproteins; D039842:Neural Cell Adhesion Molecule L1; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic