Protein: Serine/threonine-protein kinase PAK 1 (EC 2.7.11.1) (Alpha-PAK) (p21-activated kinase 1) (PAK-1) (p65-PAK) (Q13153)
Organism: Homo sapiens (Human)
Function: Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2. Phosphorylates SNAI1 at 'Ser-246' promoting its transcriptional repressor activity by increasing its accumulation in the nucleus. In podocytes, promotes NR3C2 nuclear localization. Required for atypical chemokine receptor ACKR2-induced phosphorylation of LIMK1 and cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3, maybe through CFL1 phosphorylation and inactivation. Plays a role in RUFY3-mediated facilitating gastric cancer cells migration and invasion. In response to DNA damage, phosphorylates MORC2 which activates its ATPase activity and facilitates chromatin remodeling. In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in F-actin stabilization (By similarity). In hippocampal neurons, necessary for the formation of dendritic spines and excitatory synapses; this function is dependent on kinase activity and may be exerted by the regulation of actomyosin contractility through the phosphorylation of myosin II regulatory light chain (MLC) (By similarity). Along with GIT1, positively regulates microtubule nucleation during interphase.
Subcellular location: Cytoplasm {ECO:0000269|PubMed:11896197, ECO:0000269|PubMed:23260667, ECO:0000269|PubMed:25766321}. Cell junction, focal adhesion {ECO:0000269|PubMed:11896197, ECO:0000269|PubMed:25766321}. Cell projection, lamellipodium {ECO:0000269|PubMed:11896197}. Cell membrane {ECO:0000269|PubMed:25766321}. Cell projection, ruffle membrane {ECO:0000269|PubMed:25766321}. Cell projection, invadopodium {ECO:0000269|PubMed:25766321}. Nucleus, nucleoplasm {ECO:0000269|PubMed:23260667}. Chromosome {ECO:0000269|PubMed:23260667}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269|PubMed:27012601}. Note=Colocalizes with RUFY3, F-actin and other core migration components in invadopodia at the cell periphery (PubMed:25766321). Recruited to the cell membrane by interaction with CDC42 and RAC1. Recruited to focal adhesions upon activation. Colocalized with CIB1 within membrane ruffles during cell spreading upon readhesion to fibronectin. Upon DNA damage, translocates to the nucleoplasm when phosphorylated at Thr-212 where is co-recruited with MORC2 on damaged chromatin (PubMed:23260667). Localization to the centrosome does not depend upon the presence of gamma-tubulin (PubMed:27012601). Localization of the active, but not inactive, protein to the adhesions and edge of lamellipodia is mediated by interaction with GIT1 (PubMed:11896197). {ECO:0000250|UniProtKB:P35465, ECO:0000269|PubMed:11896197, ECO:0000269|PubMed:23260667, ECO:0000269|PubMed:25766321, ECO:0000269|PubMed:27012601}.
Interaction partners:
- Cell division control protein 42 homolog
- Ras-related C3 botulinum toxin substrate 1
- SH2/SH3 adapter protein NCK1
- Ras-related C3 botulinum toxin substrate 3
- Rho guanine nucleotide exchange factor 6
- Rho guanine nucleotide exchange factor 7
- RAC-alpha serine/threonine-protein kinase
- Cytoplasmic protein NCK2
- LIM domain kinase 1
- Ras-related C3 botulinum toxin substrate 2
Sequence:
MSNNGLDIQDKPPAPPMRNTSTMIGAGSKDAGTLNHGSKPLPPNPEEKKKKDRFYRSILPGDKTNKKKEKERPEISLPSDFEHTIHVGFDAVTGEFTGMPEQWARLLQTSNITKSEQKKNPQAVLDVLEFYNSKKTSNSQKYMSFTDKSAEDYNSSNALNVKAVSETPAVPPVSEDEDDDDDDATPPPVIAPRPEHTKSVYTRSVIEPLPVTPTRDVATSPISPTENNTTPPDALTRNTEKQKKKPKMSDEEILEKLRSIVSVGDPKKKYTRFEKIGQGASGTVYTAMDVATGQEVAIKQMNLQQQPKKELIINEILVMRENKNPNIVNYLDSYLVGDELWVVMEYLAGGSLTDVVTETCMDEGQIAAVCRECLQALEFLHSNQVIHRDIKSDNILLGMDGSVKLTDFGFCAQITPEQSKRSTMVGTPYWMAPEVVTRKAYGPKVDIWSLGIMAIEMIEGEPPYLNENPLRALYLIATNGTPELQNPEKLSAIFRDFLNRCLEMDVEKRGSAKELLQHQFLKIAKPLSSLTPLIAAAKEATKNNH