| Budget Amount *help |
¥15,700,000 (Direct Cost: ¥15,700,000)
Fiscal Year 2005: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2004: ¥9,700,000 (Direct Cost: ¥9,700,000)
|
|---|
| Research Abstract |
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) By using mice bearing mutant SHPS-1 lacking most of the cytoplasmic region, we have shown that engagement of SHPS-1 (on macrophages) by CD47 (on RBCs) negatively regulates the phagocytosis of RBCs, thereby determining both the life span of individual RBCs and the number of circulating erythrocytes.
(2) Engagement of SIRPβ, a family member of SHPS-1, promotes phagocytosis in macrophages by inducing the tyrosine phosphorylation of DAP 12, Syk, and SLP-76 and the subsequent activation of a MEK-MAPK-MLCK cascade.
(3) 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 involves the activation of Rac and Cdc42, and integrins containing the β3 subunit. CD47-deficient hippocampal neurons manifested markedly impaired development of dendrites and axons. Such regulation involved, at least in part, activation of Cdc42 and Rac mediated by Src.
(4) The ectodomain of SHPS-1 has now been shown to be shed from cells in a reaction likely mediated by LPA as well as other stimuli. The shedding of the ectodomain of SHPS-1 plays an important role in regulation of cell migration and spreading by this protein.
|
