Src homology 2 domain-containing protein tyrosine phosphatase (SHP) substrate-1 (SHPS-1) is a transmembrane protein that is expressed predominantly in macrophages. Its extracellular region interacts with the transmembrane ligand CD47 expressed on the surface of adjacent cells, and its cytoplasmic region binds the protein tyrosine phosphatases SHP-1 and SHP-2. Phagocytosis of IgG- or complement-opsonized RBCs by peritoneal macrophages derived from mice that express a mutant SHPS-1 protein that lacks most of the cytoplasmic region was markedly enhanced compared with that apparent with wild-type macrophages. This effect was not observed either with CD47-deficient RBCs as the phagocytic target or in the presence of blocking Abs to SHPS-1. Depletion of SHPS-1 from wild-type macrophages by RNA interference also promoted FcγR-mediated phagocytosis of wild-type RBCs. Ligation of SHPS-1 on macrophages by CD47 on RBCs promoted tyrosine phosphorylation of SHPS-1 and its association with SHP-1, whereas tyrosine phosphorylation of SHPS-1 was markedly reduced in response to cross-linking of FcγRs. Treatment with inhibitors of PI3K or of Syk, but not with those of MEK or Src family kinases, abolished the enhancement of FcγR-mediated phagocytosis apparent in macrophages from SHPS-1 mutant mice. In contrast, FcγR-mediated tyrosine phosphorylation of Syk, Cbl, or the γ subunit of FcR was similar in macrophages from wild-type and SHPS-1 mutant mice. These results suggest that ligation of SHPS-1 on macrophages by CD47 promotes the tyrosine phosphorylation of SHPS-1 and thereby prevents the FcγR-mediated disruption of the SHPS-1-SHP-1 complex, resulting in inhibition of phagocytosis. The inhibition of phagocytosis by the SHPS-1-SHP-1 complex may be mediated at the level of Syk or PI3K signaling.
CD47 is an integrin-associated penta-transmembrane protein that possesses an immunoglobulin-like domain in its extracellular region. We have now investigated the role of CD47 in the regulation of epithelial cell spreading and migration. CD47 is colocalized with E-cadherin at cell-cell adhesion sites of epithelial cells. A Ca 2+ switch experiment showed that CD47 was endocytosed and then relocalized to cell-cell adhesion sites in a similar manner to E-cadherin. Such polarized localization of CD47 required the multiple spanning region of this protein. In contrast, dysregulation of such formation participates, in part, in the promotion of invasion and metastasis of cancer cells. In polarized epithelial cells, cell-cell adhesion is mediated by a number of adhesion molecules, such as claudin at tight junctions, and E-cadherin and nectin at adherens junctions.(2) These adhesion molecules play central roles in the maintenance of cell adhesion through homophilic binding in trans. These molecules have also been implicated as participants in intercellular signaling, which regulates cell spreading and migration by reorganization of the actin cytoskeleton.(3) In addition to these adhesion molecules, integrins, which are commonly present at the contact sites between cells and the extracellular matrix, are also localized at cell-cell adhesion sites and play multiple roles in epithelial cell functions. (4,5) CD47, also known as integrin-associated protein, was originally identified in association with the integrin αvβ3.(6) It is a member of the Ig superfamily, possessing an Ig-V-like extracellular region, five putative transmembrane domains, and a short cytoplasmic tail.(7) The extracellular region of CD47 is responsible for its association with the integrin β3 subunit. Although most CD47-mediated cellular responses likely involve the activation of integrins, in particular αvβ3 and αIIbβ3, (7) the molecular mechanism of such activation is not fully understood. CD47 is implicated in the regulation of multiple cellular processes including neutrophil migration, (8,9) platelet spreading (10) and Langerhans cell migration, (11) all of which are processes that require rearrangement of the actin cytoskeleton. More recently, in N1E-115 neuroblastoma cells or cultured neurons, it was found that CD47 promotes neurite and filopodium formation.(12) Thus, CD47 regulates multiple cell functions by controlling the actin cytoskeleton. Certain cellular responses triggered by CD47 appear to be mediated by the PTX-sensitive heterotrimeric G protein G i .( 7) In addition, Rac and Cdc42 has also been implicated to participate in the CD47-elicited promotion of polarity in B cells (13) and neurite formation. (12) In addition to integrin, the extracellular region of CD47 binds the putative ligands thrombospondin-1 (7) and SHPS-1. (14) SHPS-1 is a receptor-like transmembrane protein that contains three Ig-like domains in its extracellular region. (15) We have recently shown that binding of SHPS-1 to CD47 further enhances CD47-promoted neurite and fil...
Type 2 oculocutaneous albinism (OCA2) is an autosomal recessive disorder that results from mutations in the P gene that codes one of the melanosomal proteins, the function of which remains unknown. In this paper, we report the frequency of OCA2, 8%, among the Japanese albino population, six novel mutations containing four missense substitutions (P198L, P211L, R10W, M398I), and two splice site mutations (IVS15+1 G>A, IVS24-1 G>C). One of them, R10W, was within the putative signal peptide at the N-terminal of the P protein. This is the first report on the frequency of OCA2 in the Japanese albino population.
A 34-year-old woman with adult-onset Still's disease (AOSD) developed prurigo pigmentosa-like lesions on her chest and upper back in addition to the typical rash of AOSD. A biopsy specimen taken from the upper back showed characteristic features of prurigo pigmentosa. The eruption and fever subsided immediately after the administration of 40 mg/day prednisolone, but arthralgia persisted even after intravenous pulse methylprednisolone therapy in combination with immunosuppressive drugs. Various atypical skin rashes, including prurigo pigmentosa-like lesions, have been reported in association with AOSD. Therefore, one should carefully follow the clinical course of a patient in order not to overlook these atypical cutaneous manifestations of AOSD.
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