P21-activated kinase (PAK) (PAK)

P21-activated kinases (PAKs) are a family of evolutionary conserved serine/threonine kinases that serve as critical downstream effectors for the Rho-family GTPases, specifically RAC1 and CDC42 (UniProt P35465, O75676). The family is divided into two groups: Group I (PAK1, PAK2, and PAK3) and Group II (PAK4, PAK5, and PAK6), which differ in their activation mechanisms and structural organization (PMID: 26139440). PAKs play a fundamental role in regulating cytoskeletal dynamics, cell motility, survival, and proliferation (PMID: 28844778). In oncology, PAKs—particularly PAK1 and PAK4—are frequently overexpressed or hyperactivated, contributing to tumor growth, metastasis, and resistance to therapy (PMID: 30104715). Beyond cancer, PAK signaling is implicated in neurological disorders such as Alzheimer's disease and Fragile X syndrome, as well as in viral pathogenesis (PMID: 25135336). Therapeutic strategies targeting PAKs primarily involve small-molecule inhibitors that compete for the ATP-binding site or allosterically modulate the kinase activity, though achieving isoform selectivity remains a significant challenge in clinical development (PMID: 24631444).

Other names

p21-activated protein kinaseSTE20-like kinaseRAC/CDC42-activated kinasePAK family kinase

Small molecule inhibition via ATP-competitive binding to the catalytic domain or allosteric inhibition of the regulatory domain to prevent activation by Rho GTPases (PMID: 24631444).