PAK1

PLC-gamma1 is activated by dual phosphorylation on the tyrosine residues at positions 771, 783 and 1254 by Itk and ZAP-70 (step 14). Phosphorylated PLC-gamma1 subsequently detaches from LAT and SLP-76 and translocates to the plasma membrane by binding to phosphatidylinositol-4,5-bisphosphate (PIP2) via its PH domain (step 15). PLC-gamma1 goes on to hydrolyse PIP2 to second messengers DAG and IP3. These second messengers are involved in PKC and NF-kB activation and calcium mobilization (step 16)

PKNs play important roles in diverse functions, including regulation of cell cycle, receptor trafficking, vesicle transport and apoptosis. PKN is also involved in the ligand-dependent transcriptional activation by the androgen receptor. More than 20 proteins and several peptides have been shown to be phosphorylated by PKN1 and PKN2, including CPI-17 (Hamaguchi et al. 2000), alpha-actinin (Mukai et al. 1997), adducin (Collazos et al. 2011), CDC25C (Misaki et al. 2001), vimentin (Matsuzawa et al. 1997), TRAF1 (Kato et al. 2008), CLIP170 (Collazos et al. 2011) and EGFR (Collazos et al. 2011). There are no known substrates for PKN3 (Collazos et al. 2011)

PAK1, PAK2 and PAK3 are direct effectors of RAC1 and CDC42 GTPases. RAC1 and CDC42 bind to the CRIB domain. This binding induces a conformational change that disrupts inactive PAK homodimers and relieves autoinhibition of the catalytic carboxyl terminal domain (Manser et al. 1994, Manser et al. 1995, Zhang et al. 1998, Lei et al. 2000, Parrini et al. 2002; reviewed by Daniels and Bokoch 1999, Szczepanowska 2009). Autophosphorylation of a conserved threonine residue in the catalytic domain of PAKs (T423 in PAK1, T402 in PAK2 and T436 in PAK3) is necessary for the kinase activity of PAK1, PAK2 and PAK3. Autophosphorylation of PAK1 serine residue S144, PAK2 serine residue S141, and PAK3 serine residue S154 disrupts association of PAKs with RAC1 or CDC42 and enhances kinase activity (Lei et al. 2000, Chong et al. 2001, Parrini et al. 2002, Jung and Traugh 2005, Wang et al. 2011). LIMK1 is one of the downstream targets of PAK1 and is activated through PAK1-mediated phosphorylation of the threonine residue T508 within its activation loop (Edwards et al. 1999). Further targets are the myosin regulatory light chain (MRLC), myosin light chain kinase (MLCK), filamin, cortactin, p41Arc (a subunit of the Arp2/3 complex), caldesmon, paxillin and RhoGDI, to mention a few (Szczepanowska 2009).

Class II PAKs also have a CRIB domain, but lack a defined autoinhibitory domain and proline-rich regions. They do not require GTPases for their kinase activity, but their interaction with RAC or CDC42 affects their subcellular localization. Only conventional PAKs will be annotated here