Research for physiological roles of the CD47-SHPS-1 system.

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SHPS-1 is a transmembrane protein whose extracellular region interacts with CD47 and whose cytoplasmic region binds the protein tyrosine phosphatases SHP-1 or SHP-2. CD47 is a penta-transmembrane protein, which was originally identified as a binding partner of integrin. We have recently elucidated that CD47 and SHPS-1 constitute an intercellular communication system (the CD47-SHPS-1 system), that plays important roles in the following cell functions. In this study, we investigated the physiological roles of CD47-SHPS-1 system. The results obtained are follows :(1)The SHPS-1-SHP-2 complex positively regulated the migration of melanoma cells and other cultured cells, however engagement of SHPS-1 by CD47 prevented such regulation. Engagement of SHPS-1 by CD47 also induced the dephosphorylation of SHPS-1 and enhanced Rho activity accompanied by formation of stress fibers and adoption of a less polarized morphology. Thus, the CD47-SHPS-1 system might thus contribute to the inhibition of cel … More l migration by cell-cell contact.(2)The phagocytosis of opsonoized red blood cells (RBCs) by peritoneal macrophages (PEMs) from mice bearing mutant SHPS-1 lacking most of cytoplasmic regions (SHPS-1-Δcyto) was markedly increased, compared wild-type PEMs. In contrast, the difference between WT and the mutant was not observed when CD47-null RBC was used as a phagocytotic target or in the presence of blocking antibodies of SHPS-1. Thus, the engagement of SHPS-1 (on macrophages) by CD47 (on RBCs) negatively regulates the phagocytosis of opsonized RBCs through a manner dependent of SHP-1.(3)In primary cultured hippocampal neurons, SHPS-1 and CD47 were localized in a different manner ; the former predominantly on axons and the latter on dendrites, respectively. Exogenous expression of SHPS-1 and CD47 in cultured neurons also confirmed this observation.(4)In N1E-115 neuroblastoma cells, forced expression of CD47 induced neurite extension and filopodium formation, those were further enhanced by CD47-Fc fusion protein. Such regulation involved the activation of Rac and Cdc42, and integrins containing the β3 subunit. Less