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

SHPS-1是一种跨膜蛋白，其胞外区域与SHPS-1的配体CD47相互作用。SHPS-1的细胞质区与酪氨酸磷酸酶SHIP-1或SHP-2结合。CD47是一种五跨膜蛋白，最初被鉴定为整合素的结合伙伴。我们最近阐明CD47和hips -1构成了一个细胞间通信系统（CD47- shps -1系统），在以下细胞功能中起重要作用。在本研究中，我们探讨了CD47-SHPS-1系统的生理作用。研究结果如下：(1)CD47与hips -1相互作用，共同调控神经突发育，最终促进神经网络的形成。(2) SHIPS-1抑制巨噬细胞吞噬的胞质区域以及该区域的酪氨酸磷酸化位点是SHIPS-1抑制巨噬细胞吞噬作用不可或缺的。SHIPS-1可能调节被吞噬的靶细胞对巨噬细胞的附着。(3)表达CD47的细胞与表达ships -1的细胞接触时，CD47与SHPS-1发生反式相互作用，导致配体-受体复合物内吞作用（反式内吞作用）。这种内吞作用受网格蛋白或动力蛋白以及Rae和Cdc42的调节。(4)树突状细胞上表达的SHPS-1对Th17或Th1细胞的诱导以及NKT细胞的活化具有重要作用。

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.