p21-activated kinase (PAK)

p21-activated kinases (PAKs) are a family of serine/threonine protein kinases acting as key effectors of the small GTPases Cdc42 and Rac1. Mammals express six isoforms (PAK1-PAK6), divided into two groups (I and II) based on structural motifs and regulatory mechanisms. PAKs orchestrate diverse cellular processes, including cytoskeleton remodeling, cell proliferation, cell survival, apoptosis, and signal transduction. PAK dysregulation contributes to diseases such as cancer, cardiovascular and neurological disorders. Group I PAKs (PAK1, PAK2, PAK3) feature a shared regulatory N-terminal domain and a kinase C-terminal domain; they are activated by direct interaction with GTP-bound forms of Cdc42/Rac1, which relieves autoinhibition. PAK family proteins have garnered significant interest as therapeutic targets, particularly in oncology and neuroscience, although drug development faces challenges due to isoform redundancy and fundamental physiological roles.

Other names

PAK (generic abbreviation for family)p21-activated kinases (plural for family)PAK1, PAK2, PAK3, PAK4, PAK5, PAK6 (isoforms)STE20 (family association; sometimes used in yeast)

Inhibition of PAK enzymatic activity (ATP-competitive or allosteric inhibitors) - Modulation/disruption of PAK scaffolding and downstream signaling (e.g., cytoskeletal reorganization, apoptotic signals) - Indirect modulation via upstream effectors (e.g., Cdc42, Rac1 GTPases).