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 group A (PAK1, PAK2, PAK3) and group B (PAK4, PAK5, PAK6).

Products
Background
Gene Data

Inhibitors

Cat No Product Name / Activity
5190 FRAX 486
Potent PAK inhibitor; brain penetrant and orally bioavailable
6029 FRAX 597
Potent group I PAK inhibitor
3622 IPA 3
Group I PAK inhibitor
6005 PF 3758309 dihydrochloride
Potent PAK4 inhibitor; orally available

Other

Cat No Product Name / Activity
4212 PIR 3.5
Negative control of IPA 3 (Cat. No. 3622)

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 A - PAK1, PAK2 and PAK3; and group B - 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 :

    PAK Gene Data

    Gene Species Gene Symbol Gene Accession No. Protein Accession No.
    PAK1 Human PAK1 NM_002576 Q13153
    Mouse Pak1 NM_011035 O88643
    Rat Pak1 NM_017198 P35465
    PAK2 Human PAK2 NM_002577 Q13177
    Mouse Pak2 NM_177326 Q8CIN4
    Rat Pak2 NM_053306 Q64303
    PAK3 Human PAK3 NM_002578 O75914
    Mouse Pak3 NM_001195046 Q61036
    Rat Pak3 NM_019210 Q62829
    PAK4 Human PAK4 NM_001014831 O96013
    Mouse Pak4 NM_027470 NP_081746
    Rat Pak4 NM_001106238 NP_001099708
    PAK5 (PAK7) Human PAK7 NM_020341 Q9P286
    Mouse Pak7 NM_172858 Q8C015
    Rat Pak7 NM_001107781 NP_001101251
    PAK6 Human PAK6 NM_020168 Q9NQU5
    Mouse Pak6 NM_001033254 Q3ULB5
    Rat Pak6 NM_001106498 NP_001099968