PAKs

PAKs, or p21-activated kinases, are a family of serine/threonine kinases regulated by the small GTPases Rac and Cdc42. They participate in transducing signals from the cell membrane to control cytoskeletal dynamics, cell movement, and transcriptional programs. The family is divided into two groups: Group I, consisting of PAK1, PAK2, and PAK3, and Group II, consisting of PAK4, PAK5, and PAK6. PAKs are expressed in various tissues, with particular subtypes showing distinct patterns of expression and function.

Group I PAKs are typically activated when GTP-bound Rac or Cdc42 binds to the CRIB motif, relieving autoinhibition and promoting autophosphorylation and kinase activity. Inactive Group I PAKs often exist as dimers, and activation involves a conformational change that enables substrate phosphorylation. Group II PAKs are generally monomeric and regulated by different mechanisms, with activation less dependent on CRIB-mediated relief of autoinhibition. PAK7 is sometimes discussed as related but distinct in its regulatory features.

Functions of PAKs span cytoskeletal remodeling, including regulation of lamellipodia and filopodia formation, focal adhesion turnover, and cell migration. They also influence cell cycle progression, survival signaling, and transcriptional programs, often through cross-talk with MAPK pathways. In the nervous system, PAKs contribute to dendritic spine development and synaptic plasticity.

Clinical relevance: dysregulated PAK signaling has been linked to cancer progression and metastasis, as well as neurodevelopmental and neurodegenerative disorders. As a result, PAK inhibitors are active in research and development, with several compounds used as tools in the study of PAK function and potential therapeutic candidates in preclinical or early clinical stages.