P51817 (PRKX_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
cAMP-dependent protein kinase catalytic subunit PRKX
Short name=PrKX
Short name=Protein kinase X
Short name=Protein kinase X-linked
Short name=Serine/threonine-protein kinase PRKX
EC=2.7.11.1

Alternative name(s):
Protein kinase PKX1

Gene names

Name:	PRKX
Synonyms:	PKX1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	358 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. Ref.4 Ref.6 Ref.7 Ref.9 Ref.10 Ref.11 Ref.13
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. Ref.5 Ref.6
Enzyme regulation	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. Ref.5 Ref.6 Ref.12
Subunit structure	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). Ref.5 Ref.9 Ref.10 Ref.11 Ref.12
Subcellular location	Cytoplasm. Nucleus. Note: cAMP induces nuclear translocation. Ref.5 Ref.6 Ref.9
Tissue specificity	Widely expressed (at protein level). Specifically expressed in blood by macrophages and granulocytes according to Ref.4. Ref.1 Ref.4 Ref.7 Ref.8
Developmental stage	Expression is developmentally regulated being high and specific in a wide range of developing tissues including liver, kidney, brain and pancreas (at protein level). Ref.6 Ref.7 Ref.8
Induction	Up-regulated by phorbol 12-myristate 13-acetate (PMA). Ref.4 Ref.5 Ref.6 Ref.9 Ref.12
Post-translational modification	Phosphorylated; autophosphorylates in vitro. Ref.5 Ref.9
Involvement in disease	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.
Sequence similarities	Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cAMP subfamily. Contains 1 AGC-kinase C-terminal domain. Contains 1 protein kinase domain.
Biophysicochemical properties	Kinetic parameters: KM=127 µM for ATP (in the presence of 10 mM magnesium chloride) Ref.5 Ref.6 KM=58 µM for kemptide (in the presence of 10 mM magnesium chloride) KM=6.7 µM for kemptide (in the presence of 1 µM Br-cAMP at 30 degrees Celsius)

Ontologies

Keywords
Biological process	Angiogenesis Differentiation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Chromosomal rearrangement Polymorphism
Ligand	ATP-binding Nucleotide-binding cAMP
Molecular function	Developmental protein Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	angiogenesis Inferred from mutant phenotype Ref.13. Source: UniProtKB cell-substrate adhesion Inferred from mutant phenotype Ref.9. Source: UniProtKB endothelial cell migration Inferred from mutant phenotype Ref.13. Source: UniProtKB endothelial cell proliferation Inferred from mutant phenotype Ref.13. Source: UniProtKB epithelial tube morphogenesis Inferred from direct assay Ref.10. Source: UniProtKB kidney morphogenesis Inferred from direct assay Ref.10. Source: UniProtKB myeloid cell differentiation Inferred from direct assay Ref.4. Source: UniProtKB peptidyl-serine phosphorylation Inferred from direct assay Ref.9. Source: UniProtKB protein autophosphorylation Inferred from direct assay Ref.5Ref.9. Source: UniProtKB regulation of cell adhesion Inferred from direct assay Ref.10. Source: UniProtKB regulation of cell migration Inferred from direct assay Ref.10. Source: UniProtKB regulation of epithelial cell differentiation involved in kidney development Inferred from direct assay Ref.10. Source: UniProtKB
Cellular_component	cytoplasm Inferred from direct assay Ref.5Ref.13. Source: UniProtKB nucleus Inferred from direct assay Ref.5Ref.9Ref.13. Source: UniProtKB
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW cAMP-dependent protein kinase activity Inferred from direct assay Ref.5Ref.10. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		2	EBI-4302903,EBI-4302903
GPKOW	Q92917	2	EBI-4302903,EBI-746309
HSP90AB1	P08238	2	EBI-4302903,EBI-352572
PRKAR1A	P10644	2	EBI-4302903,EBI-476431
SMAD6	O43541	5	EBI-4302903,EBI-976374

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 358	358	cAMP-dependent protein kinase catalytic subunit PRKX		PRO_0000086582
Regions
	Domain	49 – 303	255	Protein kinase
	Domain	304 – 358	55	AGC-kinase C-terminal
	Nucleotide binding	55 – 63	9	ATP By similarity
Sites
	Active site	172	1	Proton acceptor By similarity
	Binding site	78	1	ATP By similarity
Natural variations
	Natural variant	43	1	V → A. Corresponds to variant rs3752362 [ dbSNP | Ensembl ].		VAR_061744
Experimental info
	Mutagenesis	78	1	K → R: Loss of function. Ref.6
	Mutagenesis	93	1	H → Q: Constitutive kinase activity; when associated with R-202. Ref.7
	Mutagenesis	202	1	W → R: Constitutive kinase activity; when associated with Q-93. Ref.7
	Mutagenesis	283	1	R → L: Increases the affinity for PRKAR2A and PRKAR2B. Ref.12

Sequences

	Sequence		Length	Mass (Da)
	P51817 [UniParc]. Last modified October 1, 1996. Version 1. Checksum: B603834E3541CB56	FASTA	358	40,896
	10 20 30 40 50 60 MEAPGLAQAA AAESDSRKVA EETPDGAPAL CPSPEALSPE PPVYSLQDFD TLATVGTGTF 70 80 90 100 110 120 GRVHLVKEKT AKHFFALKVM SIPDVIRLKQ EQHVHNEKSV LKEVSHPFLI RLFWTWHDER 130 140 150 160 170 180 FLYMLMEYVP GGELFSYLRN RGRFSSTTGL FYSAEIICAI EYLHSKEIVY RDLKPENILL 190 200 210 220 230 240 DRDGHIKLTD FGFAKKLVDR TWTLCGTPEY LAPEVIQSKG HGRAVDWWAL GILIFEMLSG 250 260 270 280 290 300 FPPFFDDNPF GIYQKILAGK IDFPRHLDFH VKDLIKKLLV VDRTRRLGNM KNGANDVKHH 310 320 330 340 350 RWFRSVDWEA VPQRKLKPPI VPKIAGDGDT SNFETYPEND WDTAAPVPQK DLEIFKNF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	X85545 mRNA. Translation: CAA59733.1. BC041073 mRNA. Translation: AAH41073.1.
IPI	IPI00020904.
PIR	I38121.
RefSeq	NP_005035.1. NM_005044.4.
UniGene	Hs.390788.
3D structure databases
ProteinModelPortal	P51817.
ModBase	Search...
Protein-protein interaction databases
IntAct	P51817. 4 interactions.
STRING	9606.ENSP00000262848.
PTM databases
PhosphoSite	P51817.
Polymorphism databases
DMDM	1709648.
Proteomic databases
PaxDb	P51817.
PRIDE	P51817.
Protocols and materials databases
DNASU	5613.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000262848; ENSP00000262848; ENSG00000183943.
GeneID	5613.
KEGG	hsa:5613.
UCSC	uc010nde.3. human.
Organism-specific databases
CTD	5613.
GeneCards	GC0XM003515.
H-InvDB	HIX0202211.
HGNC	HGNC:9441. PRKX.
HPA	HPA015324.
MIM	300083. gene.
neXtProt	NX_P51817.
PharmGKB	PA33786.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000233033.
HOVERGEN	HBG108317.
InParanoid	P51817.
KO	K04345.
OMA	PEDDWNK.
OrthoDB	EOG4FTW1P.
PhylomeDB	P51817.
Enzyme and pathway databases
BRENDA	2.7.11.1. 2681.
SignaLink	P51817.
Gene expression databases
Bgee	P51817.
CleanEx	HS_PRKX.
Genevestigator	P51817.
GermOnline	ENSG00000183943. Homo sapiens.
Family and domain databases
InterPro	IPR000961. AGC-kinase_C. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR002290. Ser/Thr_dual-sp_kinase_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00133. S_TK_X. 1 hit. SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS51285. 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]
ProtoNet	Search...
Other
BindingDB	P51817.
ChEMBL	CHEMBL5818.
GenomeRNAi	5613.
NextBio	21818.
SOURCE	Search...

Entry information

Entry name

PRKX_HUMAN

Accession

Primary (citable) accession number: P51817

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	May 29, 2013
This is version 121 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.