Signalling by the non-conventional p21-activated kinase 4

Abstract

<P>THE P21-ACTIVATED KINASE (PAK) FAMILY OF PROTEINS ARE CRITICAL REGULATORS OF CELL SIGNALLING DOWNSTREAM OF THE CDC42 AND RAC SUBFAMILIES OF RHO GTPASES. THE GROUP II PAKS (MAMMALIAN PAK4, 5 AND 6) IS LESS UNDERSTOOD BOTH IN TERMS OF THEIR TARGETS AND KINASE REGULATION. HERE I DEFINE NOVEL MECHANISMS OF REGULATION, NOT SEEN IN THE GROUP I PAKS.</P><P>THE UBIQUITOUS PAK4 CAN AFFECT THE ACTIN CYTOSKELETON AND IS OVER-EXPRESSED IN A NUMBER OF TUMOURS, HOWEVER THE BASIS FOR ITS ROLE IN ADHESION-INDEPENDENT GROWTH AND SURVIVAL IS NOT UNDERSTOOD. I HAVE MAPPED AND FUNCTIONALLY CHARACTERIZED ALL THE CONSERVED REGULATORY DOMAINS IN PAK4 THAT DETERMINE BOTH LOCALIZATION AND ACTIVITY OF THE KINASE. THIS INCLUDES 14-3-3 BINDING SITES THAT HAVE PROFOUND EFFECTS ON THE FUNCTION OF THE KINASE. USING ZEBRAFISH AS A MODEL SYSTEM, WE SHOW THAT PAK4 OPERATES VIA KINASE-INDEPENDENT MECHANISMS, INCLUDING NUCLEOCYTOPLASMIC SHUTTLING WHICH ASSISTS IN RELOCALIZATION OF IMPORTANT PAK4-ASSOCIATED PROTE