Structure, biochemistry, and biology of PAK kinases

Abstract

PAKs, p21-activated kinases, play central roles and act as converging junctions for discrete signals elicited on the cell surface and for a number of intracellular signaling cascades. PAKs phosphorylate a vast number of substrates and act by remodeling cytoskeleton, employing scaffolding, and relocating to distinct subcellular compartments. PAKs affect wide range of processes that are crucial to the cell from regulation of cell motility, survival, redox, metabolism, cell cycle, proliferation, transformation, stress, inflammation, to gene expression. Understandably, their dysregulation disrupts cellular homeostasis and severely impacts key cell functions, and many of those are implicated in a number of human diseases including cancers, neurological disorders, and cardiac disorders. Here we provide an overview of the members of the PAK family and their current status. We give special emphasis to PAK1 and PAK4, the prototypes of groups I and II, for their profound roles in cancer, the nervous system, and the heart. We also highlight other family members. We provide our perspective on the current advancements, their growing importance as strategic therapeutic targets, and our vision on the future of PAKs.

A PAK5–DNPEP–USP4 axis dictates breast cancer growth and metastasis

“…The p21‐activated kinases (PAKs) are a class of conserved serine/threonine protein kinases that are considered modulators of cell cycle progression, gene transcription, cell motility and cell transformation. Six mammalian PAKs have been identified, and they can be categorized into two subgroups, Group I (PAK1–3) and Group II (PAK4–6), based on sequence and structure . Studies indicate that p21‐activated kinase 5 (PAK5), the most recently identified member of the PAK family, plays an indispensable role in regulation of the cytoskeleton, microtubule stability and cell survival .…”

MicroRNA miR‐252 targets mbt to control the developmental growth of Drosophila

“…In mammals, PAK proteins are encoded by six genes (PAK 1-6) and are subdivided into two groups (group I, PAK 1-3; group II, PAK 4-6). PAK proteins are known to affect many biological processes, including cell cycle, proliferation and survival (Kumar et al, 2017). PAK proteins are known to affect many biological processes, including cell cycle, proliferation and survival (Kumar et al, 2017).…”

p21 protein‐activated kinase 1 is associated with severe regressive autism, and epilepsy

“…The p21‐activated kinase (PAK) family has six members, PAK1‐6, which function as key effectors of RHO family GTPases in mammalian cells to regulate several pathways including Ras/Raf/MEK/ERK, Wnt/β‐catenin, and likely others that have yet to be identified . PAKs are subdivided into two groups, type I (PAK1, PAK2, and PAK3) and type II (PAK4, PAK5, and PAK6); while all PAKs are involved in common signaling pathways, group I and II have different modes of regulation, different tissue distributions, and both common and unique substrates . All PAK proteins have been linked in some regard to cancers, but only PAK3 has thus far been linked to a developmental condition; variants in PAK3 cause an X‐linked form of intellectual disability (OMIM 300558) .…”

“…PAKs are subdivided into two groups, type I (PAK1, PAK2, and PAK3) and type II (PAK4, PAK5, and PAK6); while all PAKs are involved in common signaling pathways, group I and II have different modes of regulation, different tissue distributions, and both common and unique substrates . All PAK proteins have been linked in some regard to cancers, but only PAK3 has thus far been linked to a developmental condition; variants in PAK3 cause an X‐linked form of intellectual disability (OMIM 300558) . Overall, it is clear the PAK family has many essential roles and we are just beginning to realize their significant impact when dysregulated.…”