The p21- activated kinases Some of the better characterised effectors of the Rho GTPases are the p21 activated kinases (PAKs); a family of Serine/Threonine kinases implicated in multiple cellular processes through that capacity (Xxxx et al., 2014). Indeed, PAKs are involved with cell growth and proliferation, as well as with the regulation of cytoskeletal dynamics thus controlling cell morphology, migration and invasion (Xxxx et al., 2014; Xxxx and Minden, 2014). There are 6 PAK isoforms that are separated in 2 groups based on their sequence and structural homology; group I consists of PAK1-3 while group II consists of PAK4-6 (Xxxx et al., 2014). The two groups display some key structural and regulatory differences (Xxxxx‐Xxxxxx and Xxxxxxxx, 2008). All PAKs have a regulatory and a catalytic domain (figure 1.9). At the N-terminus of group I PAKs, the GTPase binding domain (GBD) can be found. The GBD also contains some over-lapping sequences with an auto-inhibitory domain (AID) that is crucial for the activation state of the kinase (Xxxxx‐Xxxxxx and Xxxxxxxx, 2008; Xxxxxx, 2003). Other regulatory components include proline rich regions that act as substrates for interacting partners with Src homology 3 (SH3) domains (Bokoch, 2003; Xxxx and Minden, 2014). The catalytic kinase domain lies at the C-terminus of all PAKs (King et al., 2014), (figure 1.9). In their inactivated state, group I PAKs exist as homo-dimers as the AID binds the kinase domain inhibiting its catalytic activity. This translates to the fact that group I PAKs have low basal activity. Binding of either Rac1 or Cdc42 induces a conformational change that releases the kinase domain from its inhibited state (Bokoch, 2003; Xxxxx et al., 1999). This in turn allows PAK1 to auto-phosphorylate at various sites including Thr 423 within the catalytic domain that maximises its enzymatic ability. Even after the dissociation of the activator Rho GTPase, PAK1 remains active to relay downstream effects (Xxxxxx, 2003; Xxxxx et al., 1999). The first N-terminal proline rich region interacts with the adaptor protein Nck (Xxxxxx et al., 1996) while the second proline rich region binds Growth Factor Receptor-bound protein 2 (Grb2) (Xxxx et al., 2003), (figure 1.9). Both interactions are enhanced upon growth factor receptor stimulation suggesting that PAK1 can translocate to the plasma membrane (Xxxxx‐Xxxxxx and Xxxxxxxx, 2008; Xxxxxx et al., 1996; Xxxx et al., 2003). Another proline rich region mediates the interaction of group I PA...
