Research for physiological roles of protein tyrosine phosphatases for cell adhesion.

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It has been suggested that tyrosine phosphorylation or dephosphorylation of proteins localized at cell-cell junctions plays an important role in the regulation of cell adhesion functions. We have been studying physiological roles of protein tyrosine phosphatases (PTPases) and discovered novel PTPases, such as SAP-1, SHP-2, and PTPH1. SAP-1 is a receptor-like PTPase, while SHP-2 is a non-transmembrane-type PTPase containing two SH2 domains. PTPH1 is also a non-transmembrane-type PTPase that contains an Ezrin-like structure and a PDZ domain in its N-terminal region. Thus, all these PTPases could be involved in the regulation of cell adhesion. In this study, we investigated the physiological roles of these three PTPases. The results obtained are follows :(1) Integrin-based cell adhesion directly regulates the catalytic activity of SAP-1. Expression of SAP-1 inhibits cell proliferation presumably through dephosphorylation of p130cas and other proteins localized at integrin-based cell adhesion sites. This inhibitory effect of SAP-1 may be related to "contact inhibition".(2) SHP-2 physiologically suppresses the activity of Rho and it thereby positively regulates the HGF/SF-induced cell scattering. In addition, Vav2 may be involved in the SHP-2-Rho pathway. We have generated knockout mice of SHPS-1, an SHP-2 substrate, and have shown that SHPS-1 is essential for the regulation of Ras and Rho.(3) We have tried to identify the proteins bound to the Ezrin domain or the PDZ domain of PTPH1 by the yeast two-hybrid system. We will analyze the function of these binding partners of PTPH1.