A new Rac target POSH is an SHS-containing scaffold protein involved in the JNK and NF-κB signalling pathways

The Rho, Pac and Cdc42 GTPases coordinately regulate the organization of the actin cytoskeleton and the JNK MAP kinase pathway. Mutational analysis of Rac has previously shown that these two activities are mediated by distinct cellular targets, though their identity is not known. Two Pac targets, p65(PAK) and MLK, are ser/thr kinases that have been reported to be capable of activating the JNK pathway. We present evidence that neither is the Pac target mediating JNK activation in Cos-1 cells, We have used yeast two-hybrid selection and identified a new target of Pac, POSH. This protein consists of four SH3 domains and ectopic expression leads to the activation of the JNK pathway and to nuclear translocation of NF-kappa B. When overexpressed in fibroblasts, POSH is a strong inducer of apoptosis. We propose that POSH acts as a scaffold protein and contributes to Pac-induced signal transduction pathways leading to diverse gene transcriptional changes.