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Protein

cAMP-dependent protein kinase catalytic subunit PRKX

Gene

PRKX

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Serine/threonine protein kinase regulated by and mediating cAMP signaling in cells. Acts through phosphorylation of downstream targets that may include CREB, SMAD6 and PKD1 and has multiple functions in cellular differentiation and epithelial morphogenesis. Regulates myeloid cell differentiation through SMAD6 phosphorylation. Involved in nephrogenesis by stimulating renal epithelial cell migration and tubulogenesis. Also involved in angiogenesis through stimulation of endothelial cell proliferation, migration and vascular-like structure formation.7 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.2 Publications

Enzyme regulationi

Binding of cAMP to the PRKAR1A or PRKAR1B regulatory subunits induces dissociation of the holoenzyme heterotetramer. The released monomeric PRKX is then active and able to phosphorylate its substrates.3 Publications

Kineticsi

  1. KM=127 µM for ATP (in the presence of 10 mM magnesium chloride)2 Publications
  2. KM=58 µM for kemptide (in the presence of 10 mM magnesium chloride)2 Publications
  3. KM=6.7 µM for kemptide (in the presence of 1 µM Br-cAMP at 30 degrees Celsius)2 Publications

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei78 – 781ATPPROSITE-ProRule annotation
    Active sitei172 – 1721Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi55 – 639ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    • ATP binding Source: UniProtKB-KW
    • cAMP-dependent protein kinase activity Source: UniProtKB

    GO - Biological processi

    • angiogenesis Source: UniProtKB
    • cell adhesion Source: UniProtKB
    • cell-substrate adhesion Source: UniProtKB
    • endothelial cell migration Source: UniProtKB
    • endothelial cell proliferation Source: UniProtKB
    • epithelial tube morphogenesis Source: UniProtKB
    • kidney morphogenesis Source: UniProtKB
    • myeloid cell differentiation Source: UniProtKB
    • peptidyl-serine phosphorylation Source: UniProtKB
    • protein autophosphorylation Source: UniProtKB
    • regulation of cell adhesion Source: UniProtKB
    • regulation of cell migration Source: UniProtKB
    • regulation of epithelial cell differentiation involved in kidney development Source: UniProtKB
    Complete GO annotation...

    Keywords - Molecular functioni

    Developmental protein, Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Angiogenesis, Differentiation

    Keywords - Ligandi

    ATP-binding, cAMP, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.11.1. 2681.
    SignaLinkiP51817.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    cAMP-dependent protein kinase catalytic subunit PRKX (EC:2.7.11.1)
    Short name:
    PrKX
    Short name:
    Protein kinase X
    Short name:
    Protein kinase X-linked
    Short name:
    Serine/threonine-protein kinase PRKX
    Alternative name(s):
    Protein kinase PKX1
    Gene namesi
    Name:PRKX
    Synonyms:PKX1
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640 Componenti: Chromosome X

    Organism-specific databases

    HGNCiHGNC:9441. PRKX.

    Subcellular locationi

    GO - Cellular componenti

    • cytoplasm Source: UniProtKB
    • nucleus Source: UniProtKB
    Complete GO annotation...

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    A chromosomal aberration involving PRKX is a cause of sex reversal disorder. Translocation t(X;Y)(p22;p11) with PRKY. Chromosomal translocations proximal to PRKY account for about 30% of the cases of sex reversal disorder in XX males and XY females.

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi78 – 781K → R: Loss of function. 1 Publication
    Mutagenesisi93 – 931H → Q: Constitutive kinase activity; when associated with R-202. 1 Publication
    Mutagenesisi202 – 2021W → R: Constitutive kinase activity; when associated with Q-93. 1 Publication
    Mutagenesisi283 – 2831R → L: Increases the affinity for PRKAR2A and PRKAR2B. 1 Publication

    Organism-specific databases

    PharmGKBiPA33786.

    Polymorphism and mutation databases

    BioMutaiPRKX.
    DMDMi1709648.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 358358cAMP-dependent protein kinase catalytic subunit PRKXPRO_0000086582Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei1 – 11N-acetylmethionine1 Publication

    Post-translational modificationi

    Phosphorylated; autophosphorylates in vitro.

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    MaxQBiP51817.
    PaxDbiP51817.
    PRIDEiP51817.

    PTM databases

    PhosphoSiteiP51817.

    Expressioni

    Tissue specificityi

    Widely expressed (at protein level). Specifically expressed in blood by macrophages and granulocytes according to PubMed:9860982.4 Publications

    Developmental stagei

    Expression is developmentally regulated being high and specific in a wide range of developing tissues including liver, kidney, brain and pancreas (at protein level).3 Publications

    Inductioni

    Up-regulated by phorbol 12-myristate 13-acetate (PMA).2 Publications

    Gene expression databases

    BgeeiP51817.
    CleanExiHS_PRKX.
    ExpressionAtlasiP51817. baseline and differential.
    GenevisibleiP51817. HS.

    Organism-specific databases

    HPAiHPA015324.

    Interactioni

    Subunit structurei

    Like other cAMP-dependent protein kinases, the inactive holoenzyme is probably composed of 2 PRKX catalytic subunits and a dimer of regulatory subunits. Interacts (cAMP-dependent) specifically with the regulatory subunits PRKAR1A and PRKAR1B. Compared to other cAMP-dependent serine/threonine protein kinases, does not interact with the 2 other PKA regulatory subunits PRKAR2A and PRKAR2B. Interacts with cAMP-dependent protein kinase inhibitor/PKI proteins; inhibits PRKX. Interacts with GPKOW. Interacts with SMAD6. Interacts with PKD1; involved in differentiation and controlled morphogenesis of the kidney. Interacts with PIN1 (via WW domain).5 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    GPKOWQ929172EBI-4302903,EBI-746309
    HSP90AB1P082382EBI-4302903,EBI-352572
    PRKAR1AP106442EBI-4302903,EBI-476431
    SMAD6O435415EBI-4302903,EBI-976374

    Protein-protein interaction databases

    BioGridi111599. 5 interactions.
    IntActiP51817. 4 interactions.
    STRINGi9606.ENSP00000262848.

    Structurei

    3D structure databases

    ProteinModelPortaliP51817.
    SMRiP51817. Positions 5-340.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini49 – 303255Protein kinasePROSITE-ProRule annotationAdd
    BLAST
    Domaini304 – 35855AGC-kinase C-terminalAdd
    BLAST

    Sequence similaritiesi

    Contains 1 AGC-kinase C-terminal domain.Curated
    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00790000122941.
    HOGENOMiHOG000233033.
    HOVERGENiHBG108317.
    InParanoidiP51817.
    KOiK04345.
    OMAiHSVDWEA.
    OrthoDBiEOG7VX8WD.
    PhylomeDBiP51817.
    TreeFamiTF313399.

    Family and domain databases

    InterProiIPR000961. AGC-kinase_C.
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view]
    PfamiPF00069. Pkinase. 1 hit.
    [Graphical view]
    SMARTiSM00133. S_TK_X. 1 hit.
    SM00220. S_TKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS51285. AGC_KINASE_CTER. 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.

    P51817-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MEAPGLAQAA AAESDSRKVA EETPDGAPAL CPSPEALSPE PPVYSLQDFD
    60 70 80 90 100
    TLATVGTGTF GRVHLVKEKT AKHFFALKVM SIPDVIRLKQ EQHVHNEKSV
    110 120 130 140 150
    LKEVSHPFLI RLFWTWHDER FLYMLMEYVP GGELFSYLRN RGRFSSTTGL
    160 170 180 190 200
    FYSAEIICAI EYLHSKEIVY RDLKPENILL DRDGHIKLTD FGFAKKLVDR
    210 220 230 240 250
    TWTLCGTPEY LAPEVIQSKG HGRAVDWWAL GILIFEMLSG FPPFFDDNPF
    260 270 280 290 300
    GIYQKILAGK IDFPRHLDFH VKDLIKKLLV VDRTRRLGNM KNGANDVKHH
    310 320 330 340 350
    RWFRSVDWEA VPQRKLKPPI VPKIAGDGDT SNFETYPEND WDTAAPVPQK

    DLEIFKNF
    Length:358
    Mass (Da):40,896
    Last modified:October 1, 1996 - v1
    Checksum:iB603834E3541CB56
    GO

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti43 – 431V → A.
    Corresponds to variant rs3752362 [ dbSNP | Ensembl ].
    VAR_061744

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    X85545 mRNA. Translation: CAA59733.1.
    BC041073 mRNA. Translation: AAH41073.1.
    CCDSiCCDS14125.1.
    PIRiI38121.
    RefSeqiNP_005035.1. NM_005044.4.
    XP_005274617.1. XM_005274560.2.
    UniGeneiHs.390788.

    Genome annotation databases

    EnsembliENST00000262848; ENSP00000262848; ENSG00000183943.
    GeneIDi5613.
    KEGGihsa:5613.
    UCSCiuc010nde.3. human.

    Keywords - Coding sequence diversityi

    Chromosomal rearrangement, Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    X85545 mRNA. Translation: CAA59733.1.
    BC041073 mRNA. Translation: AAH41073.1.
    CCDSiCCDS14125.1.
    PIRiI38121.
    RefSeqiNP_005035.1. NM_005044.4.
    XP_005274617.1. XM_005274560.2.
    UniGeneiHs.390788.

    3D structure databases

    ProteinModelPortaliP51817.
    SMRiP51817. Positions 5-340.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi111599. 5 interactions.
    IntActiP51817. 4 interactions.
    STRINGi9606.ENSP00000262848.

    Chemistry

    BindingDBiP51817.
    ChEMBLiCHEMBL5818.
    GuidetoPHARMACOLOGYi2175.

    PTM databases

    PhosphoSiteiP51817.

    Polymorphism and mutation databases

    BioMutaiPRKX.
    DMDMi1709648.

    Proteomic databases

    MaxQBiP51817.
    PaxDbiP51817.
    PRIDEiP51817.

    Protocols and materials databases

    DNASUi5613.
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000262848; ENSP00000262848; ENSG00000183943.
    GeneIDi5613.
    KEGGihsa:5613.
    UCSCiuc010nde.3. human.

    Organism-specific databases

    CTDi5613.
    GeneCardsiGC0XM003515.
    H-InvDBHIX0202211.
    HGNCiHGNC:9441. PRKX.
    HPAiHPA015324.
    MIMi300083. gene.
    neXtProtiNX_P51817.
    PharmGKBiPA33786.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00790000122941.
    HOGENOMiHOG000233033.
    HOVERGENiHBG108317.
    InParanoidiP51817.
    KOiK04345.
    OMAiHSVDWEA.
    OrthoDBiEOG7VX8WD.
    PhylomeDBiP51817.
    TreeFamiTF313399.

    Enzyme and pathway databases

    BRENDAi2.7.11.1. 2681.
    SignaLinkiP51817.

    Miscellaneous databases

    GenomeRNAii5613.
    NextBioi21818.
    PROiP51817.
    SOURCEiSearch...

    Gene expression databases

    BgeeiP51817.
    CleanExiHS_PRKX.
    ExpressionAtlasiP51817. baseline and differential.
    GenevisibleiP51817. HS.

    Family and domain databases

    InterProiIPR000961. AGC-kinase_C.
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view]
    PfamiPF00069. Pkinase. 1 hit.
    [Graphical view]
    SMARTiSM00133. S_TK_X. 1 hit.
    SM00220. S_TKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS51285. AGC_KINASE_CTER. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Publicationsi

    « Hide 'large scale' publications
    1. "The human protein kinase gene PKX1 on Xp22.3 displays Xp/Yp homology and is a site of chromosomal instability."
      Klink A., Schiebel K., Winkelmann M., Rao E., Horsthemke B., Luedecke H.-J., Claussen U., Scherer G., Rappold G.
      Hum. Mol. Genet. 4:869-878(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
      Tissue: Fetal brain.
    2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Tissue: Blood.
    3. "Abnormal XY interchange between a novel isolated protein kinase gene, PRKY, and its homologue, PRKX, accounts for one third of all (Y+)XX males and (Y-)XY females."
      Schiebel K., Winkelmann M., Mertz A., Xu X., Page D.C., Weil D., Petit C., Rappold G.A.
      Hum. Mol. Genet. 6:1985-1989(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: CHROMOSOMAL TRANSLOCATION WITH PRKY.
    4. "A lineage-specific protein kinase crucial for myeloid maturation."
      Semizarov D., Glesne D., Laouar A., Schiebel K., Huberman E.
      Proc. Natl. Acad. Sci. U.S.A. 95:15412-15417(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN MYELOID CELL DIFFERENTIATION, TISSUE SPECIFICITY, INDUCTION BY PMA.
    5. "PrKX is a novel catalytic subunit of the cAMP-dependent protein kinase regulated by the regulatory subunit type I."
      Zimmermann B., Chiorini J.A., Ma Y., Kotin R.M., Herberg F.W.
      J. Biol. Chem. 274:5370-5378(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: CATALYTIC ACTIVITY, KINETIC PARAMETERS, INTERACTION WITH PRKAR1A AND PKI, ENZYME REGULATION BY PRKAR1A AND PKI, SUBCELLULAR LOCATION, AUTOPHOSPHORYLATION.
    6. "PRKX, a phylogenetically and functionally distinct cAMP-dependent protein kinase, activates renal epithelial cell migration and morphogenesis."
      Li X., Li H.P., Amsler K., Hyink D., Wilson P.D., Burrow C.R.
      Proc. Natl. Acad. Sci. U.S.A. 99:9260-9265(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN CREB-DEPENDENT TRANSCRIPTION, FUNCTION IN RENAL EPITHELIAL CELL MIGRATION AND TUBULOGENESIS, CATALYTIC ACTIVITY, KINETIC PARAMETERS, ENZYME REGULATION, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-78, DEVELOPMENTAL STAGE.
    7. "Protein kinase X activates ureteric bud branching morphogenesis in developing mouse metanephric kidney."
      Li X., Hyink D.P., Polgar K., Gusella G.L., Wilson P.D., Burrow C.R.
      J. Am. Soc. Nephrol. 16:3543-3552(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN NEPHROGENESIS, MUTAGENESIS OF HIS-93 AND TRP-202, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
    8. "Profiles of PrKX expression in developmental mouse embryo and human tissues."
      Li W., Yu Z.X., Kotin R.M.
      J. Histochem. Cytochem. 53:1003-1009(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
    9. "Smad6 is a protein kinase X phosphorylation substrate and is required for HL-60 cell differentiation."
      Glesne D., Huberman E.
      Oncogene 25:4086-4098(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN MYELOID CELL DIFFERENTIATION, FUNCTION IN PHOSPHORYLATION OF SMAD6, AUTOPHOSPHORYLATION, SUBCELLULAR LOCATION, INTERACTION WITH GPKOW; PRKAR1A; SMAD6, INDUCTION BY PMA.
    10. "Protein kinase X (PRKX) can rescue the effects of polycystic kidney disease-1 gene (PKD1) deficiency."
      Li X., Burrow C.R., Polgar K., Hyink D.P., Gusella G.L., Wilson P.D.
      Biochim. Biophys. Acta 1782:1-9(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN NEPHROGENESIS, FUNCTION IN PHOSPHORYLATION OF PKD1, INTERACTION WITH PKD1.
    11. "Protein kinase-X interacts with Pin-1 and Polycystin-1 during mouse kidney development."
      Li X., Hyink D.P., Radbill B., Sudol M., Zhang H., Zheleznova N.N., Wilson P.D.
      Kidney Int. 76:54-62(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN NEPHROGENESIS, INTERACTION WITH PIN1.
    12. "Regulation of cAMP-dependent protein kinases: the human protein kinase X (PrKX) reveals the role of the catalytic subunit alphaH-alphaI loop."
      Diskar M., Zenn H.M., Kaupisch A., Kaufholz M., Brockmeyer S., Sohmen D., Berrera M., Zaccolo M., Boshart M., Herberg F.W., Prinz A.
      J. Biol. Chem. 285:35910-35918(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: ENZYME REGULATION, INTERACTION WITH PRKAR1A AND PRKAR1B, MUTAGENESIS OF ARG-283.
    13. "PRKX critically regulates endothelial cell proliferation, migration, and vascular-like structure formation."
      Li X., Iomini C., Hyink D., Wilson P.D.
      Dev. Biol. 356:475-485(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN ANGIOGENESIS.
    14. Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].

    Entry informationi

    Entry nameiPRKX_HUMAN
    AccessioniPrimary (citable) accession number: P51817
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 1, 1996
    Last sequence update: October 1, 1996
    Last modified: July 22, 2015
    This is version 142 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. Human chromosome X
      Human chromosome X: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.