IntroductionThe lifespan of circulating red blood cells (RBCs) is approximately 120 and 40 days in humans and mice, respectively, and is determined by their production in bone marrow (BM) and their clearance from the peripheral circulation, predominantly in the spleen and liver. [1][2][3] The production of RBCs is controlled by the primary erythropoietic regulator erythropoietin, 2,4 whereas clearance of old RBCs by the spleen is achieved mostly as a result of their specific recognition and phagocytosis by splenic macrophages. 5,6 The precise molecular mechanism by which splenic macrophages recognize senescent RBCs for phagocytosis is largely unknown, however. [1][2][3] Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1), 7,8 also known as signal-regulatory protein ␣, 9 brain immunoglobulin (Ig)-like molecule with tyrosinebased activation motifs, 10 and p84 neural adhesion molecule, 11 is a transmembrane protein that is especially abundant in macrophages. [12][13][14] The putative extracellular region of SHPS-1 comprises 3 Ig-like domains, and its cytoplasmic region contains 4 tyrosine phosphorylation sites that mediate the binding of Src homology 2 domain-containing protein tyrosine phosphatases designated SHP-1 and SHP-2. 7,9 Tyrosine phosphorylation of SHPS-1 is regulated by various growth factors and cytokines as well as by integrinmediated cell adhesion to extracellular matrix proteins. 7,9,[15][16][17][18] SHPS-1 thus functions as a docking protein to recruit and activate SHP-1 or SHP-2 at the cell membrane in response to extracellular stimuli. In macrophages, tyrosine-phosphorylated SHPS-1 binds SHP-1, 12,19,20 which is implicated in negative regulation of the functions of a variety of hematopoietic cells. [21][22][23] The complex of SHPS-1 and SHP-1 is thus thought to regulate macrophage functions in a negative manner.CD47 is a ligand for the extracellular region of SHPS-1. 24,25 This protein, which was originally identified in association with ␣v3 integrin, is also a member of the Ig superfamily, possessing an Ig-V-like extracellular domain, 5 putative membrane-spanning segments, and a short cytoplasmic tail. 26 CD47 and SHPS-1 constitute a cell-cell communication system (the CD47-SHPS-1 system) that plays important roles in a variety of cellular processes including cell migration, 27,28 adhesion of B cells, 29 and T-cell activation. 14,30 In addition, the CD47-SHPS-1 system is implicated in negative regulation of phagocytosis by macrophages. CD47 is highly expressed on the surface of RBCs, where it associates with the Rh protein complex instead of with integrins. 31 The rate of clearance of CD47-deficient RBCs from the bloodstream was found to be markedly increased compared with that of wild-type (WT) cells. 6,32 Furthermore, the phagocytosis of CD47-deficient RBCs by splenic or BM-derived macrophages was greatly enhanced Supported by a Grant-in-Aid for Scientific Research on Priority Areas Cancer; a Grant-in-Aid for Scientific Research (B); a Grant-in-Aid for Young Scie...
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),...
SAP-1 (PTPRH) is a receptor-type protein tyrosine phosphatase (RPTP) with a single catalytic domain in its cytoplasmic region and fibronectin type III-like domains in its extracellular region. The cellular localization and biological functions of this RPTP have remained unknown, however. We now show that mouse SAP-1 mRNA is largely restricted to the gastrointestinal tract and that SAP-1 protein localizes to the microvilli of the brush border in gastrointestinal epithelial cells. The expression of SAP-1 in mouse intestine is minimal during embryonic development but increases markedly after birth. SAP-1-deficient mice manifested no marked changes in morphology of the intestinal epithelium. In contrast, SAP-1 ablation inhibited tumorigenesis in mice with a heterozygous mutation of the adenomatous polyposis coli gene. These results thus suggest that SAP-1 is a microvillus-specific RPTP that regulates intestinal tumorigenesis.
We enhanced the activities of two agonist antibodies specific for the thrombopoietin receptor (c-MPL) by switching domains within their constant regions to those of different antibody isotypes. Our results suggest the importance of the hinge region in modulating agonist activity. The antibodies' thrombopoietin-like activity in vitro and in vivo, as well as the desirable pharmacokinetic profile conferred by retaining the whole-IgG structure, suggests that they provide a valuable option for treating thrombocytopenia.
SummaryThrombopoietin (TPO), or megakaryocyte growth and development factor (MGDF), has been shown to potentiate the sensitivity of normal human platelets to various agonists in vitro. The present study investigated the functional and biochemical properties of platelets from mice rendered thrombocytopenic by sublethal irradiation with regard to the reactivity to recombinant murine MGDF (rmMGDF) in vitro. During the course of reversible thrombocytopenia following irradiation, platelets from irradiated mice which had lower platelet counts and reciprocally higher plasma TPO levels showed lower reactivity to rmMGDF in agonist-induced platelet aggregation. Intravenous injections of recombinant soluble murine c-Mpl (sMpl), which has the ability to capture TPO, after irradiation restored the reactivity of platelets at the platelet nadir to rmMGDF. On the other hand, platelets prepared from normal mice 3 h after a single intravenous injection of pegylated rmMGDF did not respond to rmMGDF. There was a marked decrease in c-Mpl and Janus kinase 2 (JAK2) in platelets from irradiated mice at the platelet nadir. Similar results were observed with platelets from mice administered pegylated rmMGDF. JAK2 was only moderately decreased, however, in platelets from mice given sMpl after irradiation. These results indicate that exposure of platelets to increased endogenous TPO levels in vivo in thrombocytopenic mice leads to a reduction in the platelet reactivity to rmMGDF in vitro. Further, these results suggest that the c-Mpl-mediated signaling pathway, which is essential for the priming effect of rmMGDF, is defective in thrombocytopenic murine platelets.
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