PAK1
Description
The PAK1 (p21 (RAC1) activated kinase 1) is a protein-coding gene located on chromosome 11.
Serine/threonine-protein kinase PAK 1 is an enzyme that in humans is encoded by the PAK1 gene. PAK1 is one of six members of the PAK family of serine/threonine kinases which are broadly divided into group I (PAK1, PAK2 and PAK3) and group II (PAK4, PAK6 and PAK5/7). The PAKs are evolutionarily conserved. PAK1 localizes in distinct sub-cellular domains in the cytoplasm and nucleus. PAK1 regulates cytoskeleton remodeling, phenotypic signaling and gene expression, and affects a wide variety of cellular processes such as directional motility, invasion, metastasis, growth, cell cycle progression, angiogenesis. PAK1-signaling dependent cellular functions regulate both physiologic and disease processes, including cancer, as PAK1 is widely overexpressed and hyperstimulated in human cancer, at-large.
== Discovery == PAK1 was first discovered as an effector of the Rho GTPases in rat brain by Manser and colleagues in 1994. The human PAK1 was identified as a GTP-dependent interacting partner of Rac1 or Cdc42 in the cytosolic fraction from neutrophils, and its complementary DNA was cloned from a human placenta library by Martin and Colleagues in 1995.
== Function == PAK proteins are critical effectors that link the Rho family of GTPases (Rho GTPases) to cytoskeleton reorganization and nuclear signaling. PAK proteins, a family of serine/threonine p21-activated kinases, include PAK1, PAK2, PAK3 and PAK4.
PAK1, a protein kinase, plays a crucial role in intracellular signaling pathways downstream of integrins and receptor-type kinases. It is involved in a wide range of cellular processes, including cytoskeleton dynamics, cell adhesion, migration, proliferation, apoptosis, mitosis, and vesicle-mediated transport. PAK1 directly phosphorylates BAD, protecting cells from apoptosis. Its activation is triggered by interactions with CDC42 and RAC1, acting as a GTPase effector linking these Rho-related GTPases to the JNK MAP kinase pathway. PAK1 phosphorylates and activates MAP2K1, mediating the activation of downstream MAP kinases. It is involved in reorganizing the actin cytoskeleton, actin stress fibers, and focal adhesion complexes. PAK1 phosphorylates the tubulin chaperone TBCB, regulating microtubule biogenesis and organization of the tubulin cytoskeleton. Additionally, it plays a role in regulating insulin secretion in response to elevated glucose levels. PAK1 is part of a ternary complex, containing DVL1 and MUSK, crucial for MUSK-dependent regulation of AChR clustering during neuromuscular junction formation. Its activity is inhibited in apoptotic cells, possibly due to CDC2L1 and CDC2L2 binding. PAK1 phosphorylates MYL9/MLC2, RAF1 at 'Ser-338' and 'Ser-339', and SNAI1 at 'Ser-246'. Phosphorylation of RAF1 leads to its activation, translocation to mitochondria, phosphorylation of BAD, and binding to BCL2. Phosphorylation of SNAI1 enhances its transcriptional repressor activity by increasing nuclear accumulation. In podocytes, PAK1 promotes NR3C2 nuclear localization. It is essential for ACKR2-induced phosphorylation of LIMK1 and cofilin (CFL1), and for the upregulation of ACKR2 from the endosomal compartment to the cell membrane, enhancing chemokine uptake and degradation. In synapses, PAK1 might regulate F-actin cluster formation by SHANK3 through CFL1 phosphorylation and inactivation. It contributes to RUFY3-mediated facilitation of gastric cancer cell migration and invasion. PAK1 phosphorylates MORC2 in response to DNA damage, activating its ATPase activity and facilitating chromatin remodeling. In neurons, it regulates GABA(A) receptor synaptic stability and GABAergic inhibitory synaptic transmission through F-actin stabilization. In hippocampal neurons, PAK1 is essential for the formation of dendritic spines and excitatory synapses. This function depends on kinase activity and may involve regulating actomyosin contractility by phosphorylating myosin II regulatory light chain (MLC). Together with GIT1, PAK1 positively regulates microtubule nucleation during interphase. It phosphorylates FXR1, promoting its localization to stress granules and activity. PAK1 exists as a homodimer, with dimerization leading to autoinhibition. It is active as a monomer and interacts with GIT1. PAK1 is a component of cytoplasmic complexes containing PXN, ARHGEF7, and GIT1. It interacts with NISCH, DVL1 (mediating the formation of a DVL1, MUSK, and PAK1 ternary complex involved in AChR clustering), the caspase-cleaved p110 isoform of CDC2L1 and CDC2L2 (p110C), ARHGEF7, SCRIB, PDPK1 (via kinase domain), RAF1, NCK1 and NCK2, TBCB, BRSK2, SNAI1, CIB1 isoform 2 (via the N-terminal region), INPP5K, and gamma-tubulin. Its interaction with CIB1 is direct, promotes PAK1 activity, and occurs in a calcium-dependent manner. PAK1 interacts tightly with GTP-bound CDC42/P21 and RAC1, but not with GDP-bound forms.
PAK1 is also known as IDDMSSD, PAKalpha, alpha-PAK, p65-PAK.
