p21-activated kinases (PAKs) are a family of Cdc42/Racactivated serine/threonine kinases involved in a variety of cellular processes, such as motility, migration, and cytoskeletal reorganization (1).Various members of the PAK family are known to influence brain development and cognitive function, but there remain many unanswered questions regarding PAK functions in neurons, the significance of individual PAK isoforms, and their molecular mechanisms of action (5).A new genetic study by Huang and colleagues provides insight into how murine PAKs, specifically PAK1 and PAK3, are involved in brain development through morphogenesis of dendritic spines, as well as development of synaptic networks (4).As PAK3 mutations in humans cause mental retardation (3), the findings in this new study may lead to new approaches to treat disorders of cognitive function.On structural and biochemical grounds, the PAK family of kinases can be divided into two groups, group I (PAK1, -2, and -3) and group II (PAK4, -5, and -6) (1).All PAKs contain a highly conserved N-terminal Cdc42/Rac-binding domain and C-terminal protein kinase domain but differ substantially between these two domains.Within the group I PAKs, PAK1 and PAK3 are nearly identical in amino acid sequences (81% overall and Ͼ95% in the Cdc42/Rac-binding and kinase domains), and both are highly expressed in the brain.These features

Getting Smart about p21-Activated Kinases