The PAKs belong to a family of serine threonine kinases that were originally identified as downstream effectors of Cdc42 and Rac, which are members of Rho family, all of which are part of the Ras superfamily of small GTPases. The PAKs are broadly classified into two groups based on their structural differences and sequence homologies. The two groups are the Group I PAKs, consisting of PAKs 1-3, and Group II PAKs, consisting of PAKs 4-6. The PAKs all contain a GTPase binding domain (GBD) at the amino terminus, which binds to Cdc42 and Rac, and they contain a serine/threonine kinase domain at the amino terminal part of the protein. The serine/threonine kinase domain shares sequence similarity to yeast Ste20 which is also a Cdc42 binding protein. The group I PAKs have several domains that are not present in the group II PAKs, such as an autoinhibitory domain, proline rich domains, and binding sites for PIX, an exchange factor for Rho GTPases. The group I PAKs have strong sequence similarity to each other, while the group II PAKs are highly similar to each other in the GBD and kinase domains. One factor that differentiates the different PAK family members is their expression patterns. 
PAK4 is expressed in all tissues, and is expressed at particularly high levels during embryogenic development. PAK1 is also expressed at high levels in embryogenesis, and in some adult tissues including brain, muscle and spleen. PAK2 is also high in endothelial cells, and the other PAK family members are seen at high levels in the nervous system. PAK2 and PAK4 are essential for embryonic development, as mouse knockouts of these PAKs are embryonic lethal. In adult tissues, overexpression of PAK kinases is often linked to cancer. A CDK2-PTPN12-HER2-PAK1 signaling cascade orchestrates a crosstalk between the CDK2 and HER2 oncogenic pathways, and the proteins in this signaling pathway may be good targets for treating metastatic cancer. A specific PAK4:PDZ-RhoGEF interaction inhibits RhoA activity thereby promoting invadopodia maturation and inducing metastasis in melanoma cells.  There is also a connection between PI3 Kinase and PAKs.  In the nucleus, PAK4 upregulates β-catenin protein expression and is associated with increased TCF/LEF transcriptional activity.


1.Rane CK, Minden A. Semin Cancer Biol. 2019;54:40–49.