| Budget Amount *help |
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
SHPS-1 (SHP substrate-1) is a member of immunoglobulin (Ig) superfamily membrane proteins. Cytoplasmic region of SHPS-1 contains tyrosine residues, which are phosphorylated by src family tyrosine kinases and binds to a cytplasmic protein tyrosine phosphatase, SHP-2. Extracellular region of SHPS-1 specifically interacts with its physiological ligand, CD47, an another Ig superfamily membrane protein. SHPS-1 and CD47 are highly expressed in the brain, and constitutes an intercellular communication system (the CD47-SHPS-1 system). In this research, I analyzed the role of CD47 in regulation of neural functions. CD47 deficient neurons manifested impaired development of neurites, whereas overexpression of CD47 promoted such development. Interaction of SHPS-1 with CD47 also induced the formation of dendritic filopodia and spines. These effects of CD47 were prevented by inhibition of either Cdc42, Rac, or Src family kinases. Inhibition of FRG or Vav2, GEFs for Cdc42 and Rac, also prevented the effects of CD47 on dendritic development. These results indicate that CD47 promotes development of neurites in hippocampal neurons in a manner dependent, at least in part, on activation of Cdc42 and Rac mediated by Src as well as by FRG and Vav2. We also found that the trans-interaction of CD47 and SHPS-1 that occurred on contact of CD47-expressing cells and SHPS-1-expressing cells resulted in endocytosis of the ligand-receptor complex into either cell type. Trans-endocytosis of CD47 was mediated by clathrin and dynamin, and regulated by Rac and Cdc42. Moreover, CD47 expressed on the surface of cultured mouse hippocampal neurons was shown to undergo traps-endocytosis by neighboring astrocytes expressing endogenous SHPS-1. Our results suggest that trans-endocytosis of CD47 is responsible for removal of the CD47-SHPS-1 complex from the cell surface and hence regulates the function of the CD47-SHPS-1 system, at least in neurons and glial cells.
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