Physiological roles of CD47-SHPS-1 system, an intercellular signaling, in regulation of various cellular functions

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SHPS-1 is a transmembrane protein whose extracellular region interacts with CD47, a ligand for SHPS-1. The cytoplasmic region of SHPS-1 binds the protein tyrosine phosphatases SHIP-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 SHIPS-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) Interaction of CD47 with SHIPS-1 cooperatively regulates neurite development and eventually it contributes to formtion of neuronal networks. (2) The cytoplasmic region as well as tyrosine phosphorylation sites in this region of SHIPS-1 appear indispensable for this inhibitory action of SHIPS-1 for macrophage phagocytosis. SHIPS-1 may regulate the attachment of phagocytosed target cells to macrophages. (3) Trans-interaction of CD47 and SHPS-1 that occurred on contact of CD47-expressing cells and SHIPS-1-expressing cells results in endocytosis of the ligand-receptor complex into either cell type (trans-endocytosis). Such endocytosis is regulated by clathrin or dynamin as well as Rae and Cdc42. (4) SHPS-1 expressed on dendritic cells is important for induction of Th17 or Th1 cells as well as activation of NKT cells.