O88643 (PAK1_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified June 11, 2014. Version 132. History...
Names and origin
|Protein names||Recommended name:|
Serine/threonine-protein kinase PAK 1
CDC42/RAC effector kinase PAK-A
p21-activated kinase 1
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||545 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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. Ref.3 Ref.4 Ref.5 Ref.10 Ref.11
ATP + a protein = ADP + a phosphoprotein.
Magnesium By similarity.
Phosphorylation of Thr-84 by OXSR1 inhibits activation By similarity. Activated by binding small G proteins. Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, and enables activation by phosphorylation of Thr-423 By similarity.
Homodimer in its autoinhibited state. Active as monomer. Component of cytoplasmic complexes, which also contains PXN, ARHGEF6 and GIT1. Interacts with NISCH By similarity. Interacts with DVL1; mediates the formation of a DVL1, MUSK and PAK1 ternary complex involved in AChR clustering By similarity. Binds to the caspase-cleaved p110 isoform ofCDC2L1 and CDC2L2, p110C, but not the full-length proteins. Interacts with ARHGEF7. Interacts tightly with GTP-bound but not GDP-bound CDC42/P21 and RAC1. Probably found in a ternary complex composed of DSCAM, PAK1 and RAC1. Interacts with DSCAM (via cytoplasmic domain); the interaction is direct and enhanced in presence of RAC1. Interacts with SCRIB. Interacts with PDPK1. Interacts (via kinase domain) with RAF1. Interacts with NCK1 and NCK2. Interacts with TBCB. Interacts with CRIPAK. Interacts with BRSK2. Interacts with SNAI1. Interacts with CIB1 (via N-terminal region); the interaction is direct, promotes PAK1 activity and occurs in a calcium-dependent manner By similarity. Ref.5 Ref.6 Ref.7 Ref.9 Ref.10
Cytoplasm By similarity. Cell junction › focal adhesion By similarity. Cell membrane By similarity. Cell projection › ruffle membrane By similarity. Note: 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 By similarity.
Autophosphorylated in trans, meaning that in a dimer, one kinase molecule phosphorylates the other one. Activated by autophosphorylation at Thr-423 in response to a conformation change, triggered by interaction with GTP-bound CDC42 or RAC1. Activated by phosphorylation at Thr-423 by BRSK2 and by PDPK1. Phosphorylated by JAK2 in response to PRL; this increases PAK1 kinase activity. Phosphorylated at Ser-21 by PKB/AKT; this reduces interaction with NCK1 and association with focal adhesion sites By similarity. Ref.4 Ref.10 Ref.11
Contains 1 CRIB domain.
Contains 1 protein kinase domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Initiator methionine||1||1||Removed By similarity|
|Chain||2 – 545||544||Serine/threonine-protein kinase PAK 1||PRO_0000086461|
|Domain||75 – 88||14||CRIB|
|Domain||270 – 521||252||Protein kinase|
|Nucleotide binding||276 – 284||9||ATP By similarity|
|Region||70 – 140||71||Autoregulatory region By similarity|
|Region||70 – 105||36||GTPase-binding By similarity|
|Region||132 – 270||139||Interaction with CRIPAK By similarity|
|Active site||389||1||Proton acceptor By similarity|
|Binding site||299||1||ATP By similarity|
Amino acid modifications
|Modified residue||2||1||N-acetylserine By similarity|
|Modified residue||21||1||Phosphoserine; by PKB and autocatalysis By similarity|
|Modified residue||57||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||84||1||Phosphothreonine; by OXSR1 By similarity|
|Modified residue||131||1||Phosphotyrosine By similarity|
|Modified residue||142||1||Phosphotyrosine By similarity|
|Modified residue||144||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||149||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||153||1||Phosphotyrosine; by JAK2 By similarity|
|Modified residue||174||1||Phosphoserine By similarity|
|Modified residue||185||1||Phosphothreonine By similarity|
|Modified residue||199||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||201||1||Phosphotyrosine; by JAK2 By similarity|
|Modified residue||204||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||212||1||Phosphothreonine Ref.4|
|Modified residue||219||1||Phosphothreonine By similarity|
|Modified residue||220||1||Phosphoserine By similarity|
|Modified residue||223||1||Phosphoserine By similarity|
|Modified residue||230||1||Phosphothreonine By similarity|
|Modified residue||285||1||Phosphotyrosine; by JAK2 By similarity|
|Modified residue||423||1||Phosphothreonine; by autocatalysis, BRSK2 and PDPK1 Ref.10|
|||"Cloning, central nervous system expression and chromosomal mapping of the mouse PAK-1 and PAK-3 genes."|
Burbelo P.D., Kozak C.A., Finegold A.A., Hall A., Pirone D.M.
Gene 232:209-215(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||Lubec G., Sunyer B., Chen W.-Q.|
Submitted (JAN-2009) to UniProtKB
Cited for: PROTEIN SEQUENCE OF 204-215; 276-299; 309-320; 372-388 AND 472-489, IDENTIFICATION BY MASS SPECTROMETRY.
|||"p21-activated kinase 1 phosphorylates the death agonist bad and protects cells from apoptosis."|
Schurmann A., Mooney A.F., Sanders L.C., Sells M.A., Wang H.G., Reed J.C., Bokoch G.M.
Mol. Cell. Biol. 20:453-461(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
|||"Pak1 phosphorylation on T212 affects microtubules in cells undergoing mitosis."|
Banerjee M., Worth D., Prowse D.M., Nikolic M.
Curr. Biol. 12:1233-1239(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION AT THR-212.
|||"Regulation of AChR clustering by Dishevelled interacting with MuSK and PAK1."|
Luo Z.G., Wang Q., Zhou J.Z., Wang J., Luo Z., Liu M., He X., Wynshaw-Boris A., Xiong W.C., Lu B., Mei L.
Neuron 35:489-505(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN NEUROMUSCULAR JUNCTION DEVELOPMENT, INTERACTION WITH DVL1 AND MUSK.
|||"The integrin-binding protein Nischarin regulates cell migration by inhibiting PAK."|
Alahari S.K., Reddig P.J., Juliano R.L.
EMBO J. 23:2777-2788(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NISCH.
|||"The Down syndrome cell adhesion molecule (DSCAM) interacts with and activates Pak."|
Li W., Guan K.L.
J. Biol. Chem. 279:32824-32831(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DSCAM.
|||"Phosphoproteomic analysis of the developing mouse brain."|
Ballif B.A., Villen J., Beausoleil S.A., Schwartz D., Gygi S.P.
Mol. Cell. Proteomics 3:1093-1101(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Embryonic brain.
|||"Scrib regulates PAK activity during the cell migration process."|
Nola S., Sebbagh M., Marchetto S., Osmani N., Nourry C., Audebert S., Navarro C., Rachel R., Montcouquiol M., Sans N., Etienne-Manneville S., Borg J.-P., Santoni M.-J.
Hum. Mol. Genet. 17:3552-3565(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SCRIB.
|||"Synapses of amphids defective (SAD-A) kinase promotes glucose-stimulated insulin secretion through activation of p21-activated kinase (PAK1) in pancreatic beta-Cells."|
Nie J., Sun C., Faruque O., Ye G., Li J., Liang Q., Chang Z., Yang W., Han X., Shi Y.
J. Biol. Chem. 287:26435-26444(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH BRSK2, PHOSPHORYLATION AT THR-423.
|||"Beta-arrestin-dependent activation of the cofilin pathway is required for the scavenging activity of the atypical chemokine receptor D6."|
Borroni E.M., Cancellieri C., Vacchini A., Benureau Y., Lagane B., Bachelerie F., Arenzana-Seisdedos F., Mizuno K., Mantovani A., Bonecchi R., Locati M.
Sci. Signal. 6:RA30-RA30(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION.
|+||Additional computationally mapped references.|
|AF082077 mRNA. Translation: AAC32375.1.|
3D structure databases
|SMR||O88643. Positions 75-147, 249-541. |
Protein-protein interaction databases
|IntAct||O88643. 12 interactions.|
Protocols and materials databases
|MGI||MGI:1339975. Pak1. |
Enzyme and pathway databases
|BRENDA||22.214.171.124. 3474. |
Gene expression databases
Family and domain databases
|Gene3D||3.90.810.10. 1 hit. |
|InterPro||IPR000095. CRIB_dom. |
|Pfam||PF00786. PBD. 1 hit. |
PF00069. Pkinase. 1 hit.
|SMART||SM00285. PBD. 1 hit. |
SM00220. S_TKc. 1 hit.
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS50108. CRIB. 1 hit. |
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
|Accession||Primary (citable) accession number: O88643|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|