Analysis of protein tyrosine phosphorylation signal, which regulates synaptic function.

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SHPS-1 (SHP substrate-1) is a member of immunoglobulin superfamily membrane proteins. Cytoplasmic region of SHPS-1 contains tyrosine residues, which are phosphorylated and binds to a cytplasmic protein tyrosine phosphatase, SHP-2. SHPS-1 is highly expressed in the brain, and thought to have an important function to regulate tyrosine phosphorylation signal in the central nervous system. Extracellular region of SHPS-1 specifically interacts with its physiological ligand, CD47. CD47 is also an immunoglobulin superfamily membrane protein. This interaction between CD47 and SHPS-1 constitutes an intercellular communication system (the CD47-SHPS-1 system). In this research, we analyzed expression patterns of these two molecules by using primary cultured hippocampal neurons, and we found that SHPS-1 and CD47 were localized in a different manner; the former was predominantly on axons and the latter on dendrites, respectively. These results suggest that the CD47-SHPS-1 system acts as a directional intercellular signaling system at the interaction sites between dendrites and axons. We have also investigated the function of the CD47-SHPS-1 system in cultured neurons. We found that forced expression of CD47 promoted neurite formation. We also found that an Fc fusion protein containing the extracellular region of SHPS-1 induced filopodium formation in these neurons. Furthermore, exogenously expressed SHPS-1 and CD47 were markedly accumulated at the enlarged contact sites of axon and dendrite, each of which was derived from neurons transfected separately. All our findings suggest the CD47-SHPS-1 system regulates morphological change of neurons at their contact site, thereby regulates neuronal network formation. We are planning to further investigate the physiological importance of the CD47-SHPS-1 system in the regulation of neuronal function.