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.SHPS-1 is a transmembrane glycoprotein that is abundant in neural and myeloid tissues (1-6). This molecule is also known as SIRP␣1 (7), BIT (8), MFR (9), and p84 neural adhesion molecule (10). The cytoplasmic region of SHPS-1 contains two immunoreceptor tyrosine-based inhibitory motifs, which recruit and activate the Src homology 2 domain-containing protein-tyrosine phosphatases SHP-1 and SHP-2 in a phosphorylation-dependent manner (1, 7, 11). The putative extracellular region of this protein comprises three immunoglobulin (Ig)-like domains, of which the most amino-terminal, IgV-like domain associates with the ligand CD47, also known as integrin-associated protein (6,12,13).Tyrosine phosphorylation of SHPS-1 is induced by soluble growth factors (1,7,14,15), integrin-mediated cell adhesion (16 -18), or cross-linking of Fc␥ receptors (19). Overexpression of SHPS-1 inhibits the activation of extracellular signal-regulated kinases induced by growth factors such as insulin, epidermal growth factor, and platelet-derived growth factor (7); it also inhibits promotion of the motility and survival of glioblastoma cells by epidermal growth factor (20). Furthermore, SHPS-1 inhibits IgE-induced mediator secretion and cytokine synthesis by mast cells (21). These observations suggest that SHPS-1, presumably by recruiting SHP-1 or SHP-2, negatively modulates a wide range of cellular activation signals initiated by tyrosine kinase-coupled receptors. However, the physiological significance of these observations remains unclear.Recent studies have suggested that SHPS-1, through its association with CD47, contributes to cellular functions that depend on intercellular communication, including T cell activation (13),...