The p21-activated kinases (PAKs) are serine-threonine kinases that bind to the active forms of Cdc42 and Rac. They are divided into two groups, the first of which include PAK1, 2 and 3, and can be activated by Cdc42/Rac binding. Group 1 PAKs contain an autoinhibitory domain whose activity is regulated by Cdc42/Rac binding. The group 1 PAKs are known to be involved in cellular processes such as gene transcription, apoptosis, and cell morphology and motility. Much less is known about the second group, which includes PAK4, 5 and 6, and are not activated by Cdc42/Rac binding. Of the six PAK proteins, only PAK2 is ubiquitously expressed and cleaved by caspase-3. This cleavage removes the amino-terminal regulatory domain and generates a constitutively active kinase fragment. Recent experiments have shown that following cleavage, the active fragment is myristoylated and directed to the plasma membrane and membrane ruffles where it promotes cell death via increased signaling through the c-Jun N-terminal kinase pathway, but without compromising mitochondrial integrity.
