Attempt for regulating biologial activities by use of molecular recognition of SH2 and SH3 domains.

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We found an adaptor protein, Ash/Grb2 which transmits tyrosine kinase signals to downstream, resulting in activation of Ras. This protein has one SH2 and two SH3 domains. In this project, we attempted to clarify binding proteins to Ash/Grb2 SH3 domain, and then purified SH3-binding proteins from bovine brain. Among them, two proteins (150 kDa and 65 kDa proteins) were new. After cDNA clonings of these proteins, 150 kDa protein was found to be one of synaptojamin isozymes. On the other hand, 65 kDa protein was found to be homologous to Wiskott-Aldrich syndrome protein (WASP). We therefore named it N-WASP.N-WASP has a PH domain, GBD/CRIB motif, IQ motif, verprolin-like motif, cofilin-like motif and proline-rich sequences. It binds to Ash/Grb2 SH3 domain and is activated downstream of tyrosine kinases. Activated N-WASP polymerizes actin filament in Cdc42 dependent manner, resulting in filopodia formation.