KAPCG_HUMAN
ID KAPCG_HUMAN Reviewed; 351 AA.
AC P22612; O60850; Q5VZ02; Q86YI1;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 200.
DE RecName: Full=cAMP-dependent protein kinase catalytic subunit gamma;
DE Short=PKA C-gamma;
DE EC=2.7.11.11;
GN Name=PRKACG;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ASP-268.
RC TISSUE=Testis;
RX PubMed=2342480; DOI=10.1210/mend-4-3-465;
RA Beebe S.J., Oyen O., Sandberg M., Froysa A., Hansson V., Jahnsen T.;
RT "Molecular cloning of a tissue-specific protein kinase (C gamma) from human
RT testis -- representing a third isoform for the catalytic subunit of cAMP-
RT dependent protein kinase.";
RL Mol. Endocrinol. 4:465-475(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9598317; DOI=10.1006/geno.1998.5240;
RA Reinton N., Haugen T.B., Orstavik S., Skalhegg B.S., Hansson V.,
RA Jahnsen T., Tasken K.;
RT "The gene encoding the C gamma catalytic subunit of cAMP-dependent protein
RT kinase is a transcribed retroposon.";
RL Genomics 49:290-297(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ASP-268.
RG SeattleSNPs variation discovery resource;
RL Submitted (JUN-2006) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
RA Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP INVOLVEMENT IN BDPLT19, VARIANT BDPLT19 MET-74, AND CHARACTERIZATION OF
RP VARIANT BDPLT19 MET-74.
RX PubMed=25061177; DOI=10.1182/blood-2014-01-551820;
RA Manchev V.T., Hilpert M., Berrou E., Elaib Z., Aouba A., Boukour S.,
RA Souquere S., Pierron G., Rameau P., Andrews R., Lanza F., Bobe R.,
RA Vainchenker W., Rosa J.P., Bryckaert M., Debili N., Favier R., Raslova H.;
RT "A new form of macrothrombocytopenia induced by a germ-line mutation in the
RT PRKACG gene.";
RL Blood 124:2554-2563(2014).
RN [7]
RP VARIANTS [LARGE SCALE ANALYSIS] ASN-251 AND ASP-268.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Phosphorylates a large number of substrates in the cytoplasm
CC and the nucleus.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.11;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.11;
CC -!- ACTIVITY REGULATION: Activated by cAMP.
CC -!- SUBUNIT: A number of inactive tetrameric holoenzymes are produced by
CC the combination of homo- or heterodimers of the different regulatory
CC subunits associated with two catalytic subunits. cAMP causes the
CC dissociation of the inactive holoenzyme into a dimer of regulatory
CC subunits bound to four cAMP and two free monomeric catalytic subunits.
CC -!- INTERACTION:
CC P22612; P05067: APP; NbExp=3; IntAct=EBI-3907086, EBI-77613;
CC -!- TISSUE SPECIFICITY: Testis specific. But important tissues such as
CC brain and ovary have not been analyzed for the content of transcript.
CC -!- DISEASE: Bleeding disorder, platelet-type, 19 (BDPLT19) [MIM:616176]: A
CC disorder characterized by increased bleeding tendency due to platelet
CC dysfunction. Clinical features include epistaxis, hematomas, bleeding
CC after tooth extraction, and menorrhagia. {ECO:0000269|PubMed:25061177}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family. cAMP subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC41690.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/prkacg/";
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DR EMBL; M34182; AAC41690.1; ALT_INIT; mRNA.
DR EMBL; AJ001597; CAA04863.1; -; Genomic_DNA.
DR EMBL; DQ667175; ABG25920.1; -; Genomic_DNA.
DR EMBL; AL162730; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC039888; AAH39888.1; -; mRNA.
DR CCDS; CCDS6625.1; -.
DR PIR; B34724; OKHUCG.
DR RefSeq; NP_002723.2; NM_002732.3.
DR AlphaFoldDB; P22612; -.
DR SMR; P22612; -.
DR BioGRID; 111555; 77.
DR IntAct; P22612; 72.
DR STRING; 9606.ENSP00000366488; -.
DR BindingDB; P22612; -.
DR ChEMBL; CHEMBL2743; -.
DR GuidetoPHARMACOLOGY; 1478; -.
DR iPTMnet; P22612; -.
DR PhosphoSitePlus; P22612; -.
DR BioMuta; PRKACG; -.
DR DMDM; 33860173; -.
DR EPD; P22612; -.
DR jPOST; P22612; -.
DR MassIVE; P22612; -.
DR MaxQB; P22612; -.
DR PaxDb; P22612; -.
DR PeptideAtlas; P22612; -.
DR PRIDE; P22612; -.
DR ProteomicsDB; 54009; -.
DR Antibodypedia; 3868; 235 antibodies from 30 providers.
DR DNASU; 5568; -.
DR Ensembl; ENST00000377276.5; ENSP00000366488.2; ENSG00000165059.8.
DR GeneID; 5568; -.
DR KEGG; hsa:5568; -.
DR MANE-Select; ENST00000377276.5; ENSP00000366488.2; NM_002732.4; NP_002723.2.
DR UCSC; uc004agy.4; human.
DR CTD; 5568; -.
DR DisGeNET; 5568; -.
DR GeneCards; PRKACG; -.
DR HGNC; HGNC:9382; PRKACG.
DR HPA; ENSG00000165059; Tissue enriched (testis).
DR MalaCards; PRKACG; -.
DR MIM; 176893; gene.
DR MIM; 616176; phenotype.
DR neXtProt; NX_P22612; -.
DR OpenTargets; ENSG00000165059; -.
DR Orphanet; 438207; Severe autosomal recessive macrothrombocytopenia.
DR PharmGKB; PA33750; -.
DR VEuPathDB; HostDB:ENSG00000165059; -.
DR eggNOG; KOG0616; Eukaryota.
DR GeneTree; ENSGT00940000165129; -.
DR HOGENOM; CLU_000288_63_5_1; -.
DR InParanoid; P22612; -.
DR OMA; FLYRWGN; -.
DR OrthoDB; 963519at2759; -.
DR PhylomeDB; P22612; -.
DR TreeFam; TF313399; -.
DR BRENDA; 2.7.11.11; 2681.
DR PathwayCommons; P22612; -.
DR Reactome; R-HSA-111931; PKA-mediated phosphorylation of CREB.
DR Reactome; R-HSA-163358; PKA-mediated phosphorylation of key metabolic factors.
DR Reactome; R-HSA-163560; Triglyceride catabolism.
DR Reactome; R-HSA-163615; PKA activation.
DR Reactome; R-HSA-164378; PKA activation in glucagon signalling.
DR Reactome; R-HSA-180024; DARPP-32 events.
DR Reactome; R-HSA-381676; Glucagon-like Peptide-1 (GLP1) regulates insulin secretion.
DR Reactome; R-HSA-392517; Rap1 signalling.
DR Reactome; R-HSA-422356; Regulation of insulin secretion.
DR Reactome; R-HSA-432040; Vasopressin regulates renal water homeostasis via Aquaporins.
DR Reactome; R-HSA-4420097; VEGFA-VEGFR2 Pathway.
DR Reactome; R-HSA-442720; CREB1 phosphorylation through the activation of Adenylate Cyclase.
DR Reactome; R-HSA-5610780; Degradation of GLI1 by the proteasome.
DR Reactome; R-HSA-5610783; Degradation of GLI2 by the proteasome.
DR Reactome; R-HSA-5610785; GLI3 is processed to GLI3R by the proteasome.
DR Reactome; R-HSA-5610787; Hedgehog 'off' state.
DR Reactome; R-HSA-5621575; CD209 (DC-SIGN) signaling.
DR Reactome; R-HSA-5687128; MAPK6/MAPK4 signaling.
DR Reactome; R-HSA-8853659; RET signaling.
DR Reactome; R-HSA-8963896; HDL assembly.
DR Reactome; R-HSA-9010642; ROBO receptors bind AKAP5.
DR Reactome; R-HSA-9634597; GPER1 signaling.
DR Reactome; R-HSA-9634600; Regulation of glycolysis by fructose 2,6-bisphosphate metabolism.
DR Reactome; R-HSA-9660821; ADORA2B mediated anti-inflammatory cytokines production.
DR Reactome; R-HSA-9664323; FCGR3A-mediated IL10 synthesis.
DR Reactome; R-HSA-983231; Factors involved in megakaryocyte development and platelet production.
DR SABIO-RK; P22612; -.
DR SignaLink; P22612; -.
DR SIGNOR; P22612; -.
DR BioGRID-ORCS; 5568; 22 hits in 1105 CRISPR screens.
DR GeneWiki; PRKACG; -.
DR GenomeRNAi; 5568; -.
DR Pharos; P22612; Tchem.
DR PRO; PR:P22612; -.
DR Proteomes; UP000005640; Chromosome 9.
DR RNAct; P22612; protein.
DR Bgee; ENSG00000165059; Expressed in sperm and 17 other tissues.
DR Genevisible; P22612; HS.
DR GO; GO:0097546; C:ciliary base; TAS:Reactome.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0004679; F:AMP-activated protein kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004691; F:cAMP-dependent protein kinase activity; TAS:Reactome.
DR GO; GO:0034237; F:protein kinase A regulatory subunit binding; IBA:GO_Central.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; TAS:Reactome.
DR GO; GO:0034380; P:high-density lipoprotein particle assembly; TAS:Reactome.
DR GO; GO:0008584; P:male gonad development; TAS:ProtInc.
DR GO; GO:0010737; P:protein kinase A signaling; IBA:GO_Central.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
DR GO; GO:0003091; P:renal water homeostasis; TAS:Reactome.
DR GO; GO:0007283; P:spermatogenesis; TAS:ProtInc.
DR CDD; cd14209; STKc_PKA; 1.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR039084; PKA_C-gamma.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR044109; STKc_PKA.
DR PANTHER; PTHR24353:SF137; PTHR24353:SF137; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00133; S_TK_X; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW ATP-binding; cAMP; Disease variant; Kinase; Lipoprotein; Myristate;
KW Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase.
FT INIT_MET 1
FT /note="Removed"
FT CHAIN 2..351
FT /note="cAMP-dependent protein kinase catalytic subunit
FT gamma"
FT /id="PRO_0000086064"
FT DOMAIN 44..298
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 299..351
FT /note="AGC-kinase C-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00618"
FT ACT_SITE 167
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 50..58
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 73
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 198
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250"
FT MOD_RES 339
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250"
FT LIPID 2
FT /note="N-myristoyl glycine"
FT /evidence="ECO:0000250"
FT VARIANT 74
FT /note="I -> M (in BDPLT19; patient platelets show impaired
FT activation; dbSNP:rs724159972)"
FT /evidence="ECO:0000269|PubMed:25061177"
FT /id="VAR_072672"
FT VARIANT 251
FT /note="I -> N (in dbSNP:rs56287972)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040595"
FT VARIANT 268
FT /note="H -> D (in dbSNP:rs3730386)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:2342480, ECO:0000269|Ref.3"
FT /id="VAR_033902"
FT CONFLICT 345
FT /note="A -> P (in Ref. 5; AAH39888)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 351 AA; 40434 MW; E66BB4BFB8AF9B50 CRC64;
MGNAPAKKDT EQEESVNEFL AKARGDFLYR WGNPAQNTAS SDQFERLRTL GMGSFGRVML
VRHQETGGHY AMKILNKQKV VKMKQVEHIL NEKRILQAID FPFLVKLQFS FKDNSYLYLV
MEYVPGGEMF SRLQRVGRFS EPHACFYAAQ VVLAVQYLHS LDLIHRDLKP ENLLIDQQGY
LQVTDFGFAK RVKGRTWTLC GTPEYLAPEI ILSKGYNKAV DWWALGVLIY EMAVGFPPFY
ADQPIQIYEK IVSGRVRFPS KLSSDLKHLL RSLLQVDLTK RFGNLRNGVG DIKNHKWFAT
TSWIAIYEKK VEAPFIPKYT GPGDASNFDD YEEEELRISI NEKCAKEFSE F
