P21-activated Kinases

P21-activated kinases (PAKs), EC 2.7.11.1, are serine/threonine kinases that are effector proteins for the Rho GTPases Cdc42 and Rac. Six PAK isoforms have been identified to date, which can be split into two groups: group I - PAK1, PAK2 and PAK3; and group II - PAK4, PAK5 and PAK6. The PAK isoforms have varying levels of expression and tissue distribution, although they are all highly expressed in the nervous system.

Group A PAKs exist as homodimers in their inactive state, where their autoinhibitory domain (AID) overlaps with their GTPase binding domain (GBD). Binding of Cdc42 or Rac to the GBD, causes dissociation between the AID and dimerizing PAK, resulting in PAK monomers, which are autophosphorylated. In contrast group B PAKs are constitutively autophosphorylated, but the AID binds to the catalytic domain, maintaining PAK in an inactive conformation. Binding of Cdc42/Rac disrupts this interaction, resulting in PAK activation.

PAKs are physiologically involved in regulating the cytoskeleton, through controlling actin polymerization and therefore affecting cell shape, motility and adhesion. PAKs have a key role in neural development and morphology. Group A PAKs are involved in dendritic spine formation, while group B PAKs have a role in the formation of filopodia and neurite-like extensions in neurons. LIMK is a substrate of PAK; LIMK signaling inhibits actin depolymerization, which promotes the formation and stability of actin structures such as filopodia.

PAKs are also involved in the control of cell survival, proliferation and migration, with their abnormal expression being associated with many forms of cancer. Overexpression of PAK4 has been shown to be sufficient for oncogenesis, promoting anchorage-independent growth of fibroblasts, and increase migration and invasiveness, possibly through its activation of Aurora kinase A.

Furthermore PAK1 and PAK2 have been shown to be involved in cardiac ischemia and reperfusion injury, as well as promoting chemotaxis during inflammation.

External sources of pharmacological information for P21-activated Kinases :

• IUPHAR Receptor Code

• BJP Guide

PAK Gene Data