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O88643

- PAK1_MOUSE

UniProt

O88643 - PAK1_MOUSE

Protein

Serine/threonine-protein kinase PAK 1

Gene

Pak1

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 133 (01 Oct 2014)
      Sequence version 1 (01 Nov 1998)
      Previous versions | rss
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    Functioni

    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.5 Publications

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Cofactori

    Magnesium.By similarity

    Enzyme regulationi

    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.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei299 – 2991ATPPROSITE-ProRule annotation
    Active sitei389 – 3891Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi276 – 2849ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. collagen binding Source: UniProtKB
    3. protein binding Source: UniProtKB
    4. protein kinase activity Source: MGI
    5. protein serine/threonine kinase activity Source: UniProtKB

    GO - Biological processi

    1. actin cytoskeleton reorganization Source: UniProtKB
    2. apoptotic process Source: UniProtKB-KW
    3. branching morphogenesis of an epithelial tube Source: UniProtKB
    4. dendrite development Source: MGI
    5. exocytosis Source: UniProtKB-KW
    6. negative regulation of cell proliferation involved in contact inhibition Source: UniProtKB
    7. neuromuscular junction development Source: MGI
    8. positive regulation of intracellular estrogen receptor signaling pathway Source: UniProtKB
    9. positive regulation of JUN kinase activity Source: UniProtKB
    10. positive regulation of peptidyl-serine phosphorylation Source: UniProtKB
    11. positive regulation of protein phosphorylation Source: UniProtKB
    12. positive regulation of stress fiber assembly Source: UniProtKB
    13. protein autophosphorylation Source: UniProtKB
    14. protein phosphorylation Source: UniProtKB
    15. receptor clustering Source: MGI
    16. wound healing Source: UniProtKB

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Apoptosis, Exocytosis

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.11.1. 3474.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Serine/threonine-protein kinase PAK 1 (EC:2.7.11.1)
    Alternative name(s):
    Alpha-PAK
    CDC42/RAC effector kinase PAK-A
    p21-activated kinase 1
    Short name:
    PAK-1
    p65-PAK
    Gene namesi
    Name:Pak1
    Synonyms:Paka
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Unplaced

    Organism-specific databases

    MGIiMGI:1339975. Pak1.

    Subcellular locationi

    Cytoplasm By similarity. Cell junctionfocal adhesion By similarity. Cell membrane By similarity. Cell projectionruffle 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.By similarity

    GO - Cellular componenti

    1. axon Source: MGI
    2. cell-cell junction Source: UniProtKB
    3. cytoplasm Source: UniProtKB
    4. focal adhesion Source: MGI
    5. Golgi apparatus Source: UniProtKB
    6. growth cone Source: MGI
    7. nucleus Source: MGI
    8. plasma membrane Source: UniProtKB
    9. ruffle Source: UniProtKB
    10. ruffle membrane Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Cell junction, Cell membrane, Cell projection, Cytoplasm, Membrane

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11RemovedBy similarity
    Chaini2 – 545544Serine/threonine-protein kinase PAK 1PRO_0000086461Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21N-acetylserineBy similarity
    Modified residuei21 – 211Phosphoserine; by PKB and autocatalysisBy similarity
    Modified residuei57 – 571Phosphoserine; by autocatalysisBy similarity
    Modified residuei84 – 841Phosphothreonine; by OXSR1By similarity
    Modified residuei131 – 1311PhosphotyrosineBy similarity
    Modified residuei142 – 1421PhosphotyrosineBy similarity
    Modified residuei144 – 1441Phosphoserine; by autocatalysisBy similarity
    Modified residuei149 – 1491Phosphoserine; by autocatalysisBy similarity
    Modified residuei153 – 1531Phosphotyrosine; by JAK2By similarity
    Modified residuei174 – 1741PhosphoserineBy similarity
    Modified residuei185 – 1851PhosphothreonineBy similarity
    Modified residuei199 – 1991Phosphoserine; by autocatalysisBy similarity
    Modified residuei201 – 2011Phosphotyrosine; by JAK2By similarity
    Modified residuei204 – 2041Phosphoserine; by autocatalysisBy similarity
    Modified residuei212 – 2121Phosphothreonine2 Publications
    Modified residuei219 – 2191PhosphothreonineBy similarity
    Modified residuei220 – 2201PhosphoserineBy similarity
    Modified residuei223 – 2231PhosphoserineBy similarity
    Modified residuei230 – 2301PhosphothreonineBy similarity
    Modified residuei285 – 2851Phosphotyrosine; by JAK2By similarity
    Modified residuei423 – 4231Phosphothreonine; by autocatalysis, BRSK2 and PDPK12 Publications

    Post-translational modificationi

    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.By similarity

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    MaxQBiO88643.
    PaxDbiO88643.
    PRIDEiO88643.

    PTM databases

    PhosphoSiteiO88643.

    Expressioni

    Gene expression databases

    CleanExiMM_PAK1.
    GenevestigatoriO88643.

    Interactioni

    Subunit structurei

    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 of CDC2L1 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.By similarity

    Protein-protein interaction databases

    DIPiDIP-32847N.
    IntActiO88643. 12 interactions.
    MINTiMINT-193245.
    STRINGi10090.ENSMUSP00000033040.

    Structurei

    3D structure databases

    ProteinModelPortaliO88643.
    SMRiO88643. Positions 75-147, 249-541.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini75 – 8814CRIBPROSITE-ProRule annotationAdd
    BLAST
    Domaini270 – 521252Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni70 – 14071Autoregulatory regionBy similarityAdd
    BLAST
    Regioni70 – 10536GTPase-bindingBy similarityAdd
    BLAST
    Regioni132 – 270139Interaction with CRIPAKBy similarityAdd
    BLAST

    Sequence similaritiesi

    Contains 1 CRIB domain.PROSITE-ProRule annotation
    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    HOGENOMiHOG000234202.
    HOVERGENiHBG108518.
    InParanoidiO88643.
    PhylomeDBiO88643.

    Family and domain databases

    Gene3Di3.90.810.10. 1 hit.
    InterProiIPR000095. CRIB_dom.
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view]
    PfamiPF00786. PBD. 1 hit.
    PF00069. Pkinase. 1 hit.
    [Graphical view]
    SMARTiSM00285. PBD. 1 hit.
    SM00220. S_TKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS50108. CRIB. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    O88643-1 [UniParc]FASTAAdd to Basket

    « Hide

    MSNNGVDIQD KPPAPPMRNT STMIGAGSKD TGTLNHGSKP LPPNPEEKKK    50
    KDRFYRSILP GDKTNKKREK ERPEISLPSD FEHTIHVGFD AVTGEFTGMP 100
    EQWARLLQTS NITKSEQKKN PQAVLDVLEF YNSKKTSNSK KYMSFTDKSA 150
    EDYNSSNTLN VKTVSETPAV PPVSEDDEDD DDDATPPPVI APRPEHTKSV 200
    YTRSVIEPLP VTPTRDVATS PISPTENNTT PPDALTRNTE KQKKKPKMSD 250
    EEILEKLRSI VSVGDPKKKY TPFEKIGQGA SGTVYTAMDV ATGQEVAIKQ 300
    MNLQQQPKKE LIINEILVMR ENKNPNIVNY LDSYLVGDEL WVVMEYLAGG 350
    SLTDVVTETC MDEGQIAAVC RECLQALEFL HSNQVIHRDI KSDNILLGMD 400
    GSVKLTDFGF CAQITPEQSK RSTMVGTPYW MAPEVVTRKA YGPKVDIWSL 450
    GIMAIEMIEG EPPYLNENPL RALYLIATNG TPELQNPEKL SAIFRDFLQC 500
    CLEMDVEKRG SAKELLQHQF LKIAKPLSSL TPLMHAAKEA TKNNH 545
    Length:545
    Mass (Da):60,737
    Last modified:November 1, 1998 - v1
    Checksum:iA4861289534C3819
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF082077 mRNA. Translation: AAC32375.1.
    UniGeneiMm.260227.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF082077 mRNA. Translation: AAC32375.1 .
    UniGenei Mm.260227.

    3D structure databases

    ProteinModelPortali O88643.
    SMRi O88643. Positions 75-147, 249-541.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    DIPi DIP-32847N.
    IntActi O88643. 12 interactions.
    MINTi MINT-193245.
    STRINGi 10090.ENSMUSP00000033040.

    PTM databases

    PhosphoSitei O88643.

    Proteomic databases

    MaxQBi O88643.
    PaxDbi O88643.
    PRIDEi O88643.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Organism-specific databases

    MGIi MGI:1339975. Pak1.

    Phylogenomic databases

    eggNOGi COG0515.
    HOGENOMi HOG000234202.
    HOVERGENi HBG108518.
    InParanoidi O88643.
    PhylomeDBi O88643.

    Enzyme and pathway databases

    BRENDAi 2.7.11.1. 3474.

    Miscellaneous databases

    PROi O88643.
    SOURCEi Search...

    Gene expression databases

    CleanExi MM_PAK1.
    Genevestigatori O88643.

    Family and domain databases

    Gene3Di 3.90.810.10. 1 hit.
    InterProi IPR000095. CRIB_dom.
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view ]
    Pfami PF00786. PBD. 1 hit.
    PF00069. Pkinase. 1 hit.
    [Graphical view ]
    SMARTi SM00285. PBD. 1 hit.
    SM00220. S_TKc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF56112. SSF56112. 1 hit.
    PROSITEi PS50108. CRIB. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "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].
    2. 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.
      Strain: OF1.
      Tissue: Hippocampus.
    3. "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.
    4. "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.
    5. "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.
    6. "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.
    7. "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.
    8. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Embryonic brain.
    9. Cited for: INTERACTION WITH SCRIB.
    10. "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.
    11. "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.

    Entry informationi

    Entry nameiPAK1_MOUSE
    AccessioniPrimary (citable) accession number: O88643
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: December 15, 1998
    Last sequence update: November 1, 1998
    Last modified: October 1, 2014
    This is version 133 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Allosteric enzyme, Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    3. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3