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PRKAR1A (protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1))

Identity

Other namesR1A
CAR
CNC1
MGC17251
PKR1
PRKAR1
TSE1
HGNC (Hugo) PRKAR1A
LocusID (NCBI) 5573
Location 17q24.2
Location_base_pair Starts at 66508520 and ends at 66529570 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
Description The RI alpha gene is composed of 10 coding exons of varying lengths, separated by introns, giving the gene a total length of at least 21 kb.
Transcription By alternative splicing, the PRKAR1A gene encodes 3 types of transcripts that all translate in the same protein.

Protein

 
Description 48 kDa ; contains two tandem cAMP-binding domains at the C-terminus and the dimerization domain at the N-terminus that serves also as a docking site for A Kinase Anchoring Proteins (AKAPs).
 
Expression Ubiquitously expressed, in particular in brain, endocrine tissues, adipose tissue and bone.
Localisation Predominantly cytoplasmic; nuclear traslocation possible.
Function Two regulatory subunits bind to two catalytic subunits forming an heterotetramer, the inactive holoenzyme protein kinase A (PKA) or cyclic AMP-dependent protein kinase. PKA activation occurs when 2 cAMP molecules bind to each regulatory subunit, eliciting a reversible conformational change that releases the now active catalytic subunits. Four different regulatory subunits and three catalytic subunits of PKA have been identified in humans. The protein encoded by PRKAR1A is just one of the four possible regulatory subunits of the PKA tetramer; however, PRKAR1A is the most abundant and widely expressed PKA subunit. Although its other functions are not fully elucidated yet, PRKAR1A may act as a tumor-suppressor gene in Carney complex (CNC) and in sporadic (non-CNC-related) adrenal and thyroid tumors.
Homology Prkar1a, Mus musculus
Gene conserved in Mammalia: M.musculus-81.36%; R.norvegicus-97.38%; C.elegans-57.91%; D.melanogaster-72.07%; S. cerevisiae-37.41%

Mutations

Germinal Most mutations are null alleles; they are dispersed throughout the coding region of the gene.
Somatic Many of tumors that develop in patients with Carney complex and PPNAD (see below) show loss of heterozygosity; somatic mutations in the PRKARIA gene have been reported in three cases of sporadic adrenocortical tumors.

Implicated in

Entity Carney complex syndrome, type I
Disease A multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, psammomatous melanotic schwannomas and some other tumors.
Prognosis According to the severity of the disease in a given patient, and to the quality of a regular follow up; life span is decreased in patients with CNC. 57% of the deaths are due to heart related causes; others due to the postoperative complications or evolution of the malignant process; presymptomatic diagnosis improves survival data and might prevent earlier the main causes of death in this disease.
Cytogenetics Limited data; some of myxomas and PPNAD from CNC patients showed telomeric associations, dicentric chromosomes, aneuploidy, polyploidy and chromosomal rearrangements.
Hybrid/Mutated Gene Half of CNC patients show PRKARIA mutations.
Oncogenesis PRKARIA is frequently affected by bi-allelic inactivation in tumors of CNC patients. However 1 kindred was described where a splice site mutation led to exon 6 skipping and an expressed shorter PRKAR1A protein. The mutant protein was present in patients' leukocytes and tumors, and in vitro studies indicated that the mutant PRKAR1A activated cAMP-dependent PKA signaling at the nuclear level. Along with the lack of allelic loss at the PRKAR1A locus in most of the tumors from this kindred, these data suggested that alteration of PRKAR1A function, not only its complete loss, is sufficient for augmenting PKA activity leading to tumorigenesis in tissues in patients with CNC.
  
Entity PPNAD - Primary pigmented nodular adrenocortical disease Primary pigmented nodular adrenocortical disease
Disease PPNAD is a cause of ACTH-independent Cushing's syndrome. This condition can be difficult to diagnose because hypercortisolism may be periodic and adrenal imaging may not demonstrate an adrenal tumor.
Hybrid/Mutated Gene Inactivating PRKAR1A germline mutations are frequent in sporadic and isolated cases of PPNAD.
Oncogenesis Both alleles are frequently inactivated. The wild-type allele can be inactivated by somatic mutations, consistent with the hypothesis of the gene being a tumor suppressor gene.
  
Entity Adrenocortical tumors, sporadic
Disease Patients frequently present with ACTH-independent Cushing's syndrome.
Hybrid/Mutated Gene Somatic mutations in the PRKAR1A gene were identified in 3 cases of sporadic adrenocortical tumor. All 3 mutations predicted premature termination of the protein. 17q23-24 loss-of-heterozygosity is a frequent event in adrenal carcinomas.
Oncogenesis Haploinsufficiency of PRKARIA and a reversal of the ratio of R1A to R2B have been proposed to cause tumorigenesis, at least in some cases.
  
Entity Myxoma, intracardiac
Disease Benign neoplasms that occur in 7 per 10,000 individuals. These slowely proliferating lesions arise from subendocardial pluripotent primitive mesenchymal cells, which can differentiate within myxomas along a variety of lineages including epithelial, hematopoietic, and muscular.
Prognosis Life span is decreased in patients with myxomas. Morbidity and mortality are the result of embolic stroke, heart failure due to intracardiac obstruction, and rheumatologic symptoms attributed to myxoma-mediated production of IL-6.
Cytogenetics Limited data; 15 cases of myxomas contained clonal numerical and structural abnormalities including telomeric associations.
Hybrid/Mutated Gene Mutations of PRKARIA detected in the coding region of the gene, exons 5, 7 and 8.
Oncogenesis No somatic mutations were detected in cardiac myxomas; haploinsufficiency of PRKARIA and a reversal of the ratio of RIA to R2B have been proposed may contribute in tumorigenesis.
  
Entity Papillary thyroid carcinoma
Cytogenetics Reciprocal translocation between chromosomes 10 and 17
Hybrid/Mutated Gene RET/PTC2 is formed by the fusion of the RET tyrosine kinase domain with part of the RI-alpha regulatory subunit
Abnormal Protein RET/PTC2
Oncogenesis The fusion of the RET tyrosine kinase domain with a portion of the RIA gene leads to the expression of RET in the thyroid cells, where it is normally transcriptionally silent.
  

Breakpoints

 

Other Leukemias implicated (Data extracted from papers in the Atlas)

Leukemias t0817q24q22ID1494

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors ProstateOverviewID5041 ProstateOverviewID5041

External links

Nomenclature
HGNC (Hugo)PRKAR1A   9388
Cards
AtlasPRKAR1AID387
Entrez_Gene (NCBI)PRKAR1A  5573  protein kinase, cAMP-dependent, regulatory, type I, alpha
GeneCards (Weizmann)PRKAR1A
Ensembl (Hinxton)ENSG00000108946 [Gene_View]  chr17:66508520-66529570 [Contig_View]  PRKAR1A [Vega]
ICGC DataPortalENSG00000108946
cBioPortalPRKAR1A
AceView (NCBI)PRKAR1A
Genatlas (Paris)PRKAR1A
WikiGenes5573
SOURCE (Princeton)NM_001276289 NM_001276290 NM_001278433 NM_002734 NM_212471 NM_212472
Genomic and cartography
GoldenPath (UCSC)PRKAR1A  -  17q24.2   chr17:66508520-66529570 +  17q23-q24   [Description]    (hg19-Feb_2009)
EnsemblPRKAR1A - 17q23-q24 [CytoView]
Mapping of homologs : NCBIPRKAR1A [Mapview]
OMIM101800   160980   188550   188830   255960   610489   
Gene and transcription
Genbank (Entrez)A12295 AA015682 AI074326 AK097580 AK124586
RefSeq transcript (Entrez)NM_001276289 NM_001276290 NM_001278433 NM_002734 NM_212471 NM_212472
RefSeq genomic (Entrez)AC_000149 NC_000017 NC_018928 NG_007093 NT_010783 NW_001838454 NW_004929407
Consensus coding sequences : CCDS (NCBI)PRKAR1A
Cluster EST : UnigeneHs.745160 [ NCBI ]
CGAP (NCI)Hs.745160
Alternative Splicing : Fast-db (Paris)GSHG0012767
Alternative Splicing GalleryENSG00000108946
Gene ExpressionPRKAR1A [ NCBI-GEO ]     PRKAR1A [ SEEK ]   PRKAR1A [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP10644 (Uniprot)
NextProtP10644  [Medical]
With graphics : InterProP10644
Splice isoforms : SwissVarP10644 (Swissvar)
Domaine pattern : Prosite (Expaxy)CNMP_BINDING_1 (PS00888)    CNMP_BINDING_2 (PS00889)    CNMP_BINDING_3 (PS50042)   
Domains : Interpro (EBI)cAMP/cGMP_kin [organisation]   cAMP_dep_PK_reg_su [organisation]   cAMP_dep_PK_reg_su_I/II_a/b [organisation]   cNMP-bd-like [organisation]   cNMP-bd_CS [organisation]   cNMP-bd_dom [organisation]   RmlC-like_jellyroll [organisation]  
Related proteins : CluSTrP10644
Domain families : Pfam (Sanger)cNMP_binding (PF00027)    RIIa (PF02197)   
Domain families : Pfam (NCBI)pfam00027    pfam02197   
Domain families : Smart (EMBL)cNMP (SM00100)  RIIa (SM00394)  
DMDM Disease mutations5573
Blocks (Seattle)P10644
Human Protein AtlasENSG00000108946 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP10644
HPRD01786
IPIIPI00021831   
Protein Interaction databases
DIP (DOE-UCLA)P10644
IntAct (EBI)P10644
FunCoupENSG00000108946
BioGRIDPRKAR1A
InParanoidP10644
Interologous Interaction database P10644
IntegromeDBPRKAR1A
STRING (EMBL)PRKAR1A
Ontologies - Pathways
Ontology : AmiGOmesoderm formation  cAMP-dependent protein kinase inhibitor activity  protein binding  cytosol  plasma membrane  cAMP-dependent protein kinase complex  energy reserve metabolic process  regulation of transcription from RNA polymerase II promoter  water transport  female meiotic division  signal transduction  epidermal growth factor receptor signaling pathway  activation of phospholipase C activity  blood coagulation  fibroblast growth factor receptor signaling pathway  cAMP-dependent protein kinase regulator activity  membrane  cAMP binding  AMP-activated protein kinase complex  neuromuscular junction  ubiquitin protein ligase binding  activation of protein kinase A activity  protein kinase A catalytic subunit binding  intracellular signal transduction  protein complex  small molecule metabolic process  innate immune response  sarcomere organization  negative regulation of meiosis  neurotrophin TRK receptor signaling pathway  regulation of insulin secretion  transmembrane transport  cardiac muscle cell proliferation  cellular response to glucagon stimulus  negative regulation of cAMP-dependent protein kinase activity  
Ontology : EGO-EBImesoderm formation  cAMP-dependent protein kinase inhibitor activity  protein binding  cytosol  plasma membrane  cAMP-dependent protein kinase complex  energy reserve metabolic process  regulation of transcription from RNA polymerase II promoter  water transport  female meiotic division  signal transduction  epidermal growth factor receptor signaling pathway  activation of phospholipase C activity  blood coagulation  fibroblast growth factor receptor signaling pathway  cAMP-dependent protein kinase regulator activity  membrane  cAMP binding  AMP-activated protein kinase complex  neuromuscular junction  ubiquitin protein ligase binding  activation of protein kinase A activity  protein kinase A catalytic subunit binding  intracellular signal transduction  protein complex  small molecule metabolic process  innate immune response  sarcomere organization  negative regulation of meiosis  neurotrophin TRK receptor signaling pathway  regulation of insulin secretion  transmembrane transport  cardiac muscle cell proliferation  cellular response to glucagon stimulus  negative regulation of cAMP-dependent protein kinase activity  
Pathways : BIOCARTAMultiple antiapoptotic pathways from IGF-1R signaling lead to BAD phosphorylation [Genes]    NFAT and Hypertrophy of the heart (Transcription in the broken heart) [Genes]    Sonic Hedgehog (Shh) Pathway [Genes]    Neuropeptides VIP and PACAP inhibit the apoptosis of activated T cells [Genes]    Activation of Csk by cAMP-dependent Protein Kinase Inhibits Signaling through the T Cell Receptor [Genes]    GATA3 participate in activating the Th2 cytokine genes expression [Genes]    ChREBP regulation by carbohydrates and cAMP [Genes]    Transcription factor CREB and its extracellular signals [Genes]    Attenuation of GPCR Signaling [Genes]    Regulation of BAD phosphorylation [Genes]    Repression of Pain Sensation by the Transcriptional Regulator DREAM [Genes]    Signaling Pathway from G-Protein Families [Genes]    How Progesterone Initiates the Oocyte Maturation [Genes]    Nitric Oxide Signaling Pathway [Genes]    Mechanism of Gene Regulation by Peroxisome Proliferators via PPARa(alpha) [Genes]    Activation of cAMP-dependent protein kinase, PKA [Genes]    mCalpain and friends in Cell motility [Genes]    Actions of Nitric Oxide in the Heart [Genes]    Cystic fibrosis transmembrane conductance regulator (CFTR) and beta 2 adrenergic receptor (b2AR) pathway [Genes]    Regulation of ck1/cdk5 by type 1 glutamate receptors [Genes]    Phospholipase C-epsilon pathway [Genes]    Stathmin and breast cancer resistance to antimicrotubule agents [Genes]    Transcription Regulation by Methyltransferase of CARM1 [Genes]   
Pathways : KEGGApoptosis    Insulin signaling pathway   
Protein Interaction DatabasePRKAR1A
Wikipedia pathwaysPRKAR1A
Gene fusion - rearrangments
Rearrangement : COSMICPRKAR1A [17q24.2]  -  RET [10q11.21]  
  [COSF1511] [COSF1512] 
Rearrangement : TICdbPRKAR1A [17q24.2]  -  RARA [1p35.3]
Rearrangement : TICdbPRKAR1A [17q24.2]  -  RET [1q21.3]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)PRKAR1A
snp3D : Map Gene to Disease5573
SNP (GeneSNP Utah)PRKAR1A
SNP : HGBasePRKAR1A
Genetic variants : HAPMAPPRKAR1A
Exome VariantPRKAR1A
1000_GenomesPRKAR1A 
ICGC programENSG00000108946 
Cancer Gene: CensusPRKAR1A 
Somatic Mutations in Cancer : COSMICPRKAR1A 
CONAN: Copy Number AnalysisPRKAR1A 
Mutations and Diseases : HGMDPRKAR1A
Genomic VariantsPRKAR1A  PRKAR1A [DGVbeta]
dbVarPRKAR1A
ClinVarPRKAR1A
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM101800    160980    188550    188830    255960    610489   
MedgenPRKAR1A
GENETestsPRKAR1A
Disease Genetic AssociationPRKAR1A
Huge Navigator PRKAR1A [HugePedia]  PRKAR1A [HugeCancerGEM]
General knowledge
Homologs : HomoloGenePRKAR1A
Homology/Alignments : Family Browser (UCSC)PRKAR1A
Phylogenetic Trees/Animal Genes : TreeFamPRKAR1A
Chemical/Protein Interactions : CTD5573
Chemical/Pharm GKB GenePA33754
Clinical trialPRKAR1A
Cancer Resource (Charite)ENSG00000108946
Other databases
Probes
Litterature
PubMed187 Pubmed reference(s) in Entrez
CoreMinePRKAR1A
iHOPPRKAR1A
OncoSearchPRKAR1A

Bibliography

The tissue-specific extinguisher locus TSE1 encodes a regulatory subunit of cAMP-dependent protein kinase.
Boshart M, Weih F, Nichols M, Schˆºtz G
Cell. 1991 ; 66 (5) : 849-859.
PMID 1832337
 
Subtractive hybridization cloning of a tissue-specific extinguisher: TSE1 encodes a regulatory subunit of protein kinase A.
Jones KW, Shapero MH, Chevrette M, Fournier RE
Cell. 1991 ; 66 (5) : 861-872.
PMID 1889088
 
Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A.
Bongarzone I, Monzini N, Borrello MG, Carcano C, Ferraresi G, Arighi E, Mondellini P, Della Porta G, Pierotti MA
Molecular and cellular biology. 1993 ; 13 (1) : 358-366.
PMID 7678053
 
Frequent activation of ret protooncogene by fusion with a new activating gene in papillary thyroid carcinomas.
Bongarzone I, Butti MG, Coronelli S, Borrello MG, Santoro M, Mondellini P, Pilotti S, Fusco A, Della Porta G, Pierotti MA
Cancer research. 1994 ; 54 (11) : 2979-2985.
PMID 8187085
 
PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas.
Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, Pierotti MA, Della Porta G, Fusco A, Vecchio G
Cell. 1990 ; 60 (4) : 557-563.
PMID 2406025
 
Identification of a novel genetic locus for familial cardiac myxomas and Carney complex.
Casey M, Mah C, Merliss AD, Kirschner LS, Taymans SE, Denio AE, Korf B, Irvine AD, Hughes A, Carney JA, Stratakis CA, Basson CT
Circulation. 1998 ; 98 (23) : 2560-2566.
PMID 9843463
 
RET/PTC and RET tyrosine kinase expression in adult papillary thyroid carcinomas.
Learoyd DL, Messina M, Zedenius J, Guinea AI, Delbridge LW, Robinson BG
The Journal of clinical endocrinology and metabolism. 1998 ; 83 (10) : 3631-3635.
PMID 9768676
 
Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex.
Casey M, Vaughan CJ, He J, Hatcher CJ, Winter JM, Weremowicz S, Montgomery K, Kucherlapati R, Morton CC, Basson CT
The Journal of clinical investigation. 2000 ; 106 (5) : R31-R38.
PMID 10974026
 
Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the carney complex.
Kirschner LS, Sandrini F, Monbo J, Lin JP, Carney JA, Stratakis CA
Human molecular genetics. 2000 ; 9 (20) : 3037-3046.
PMID 11115848
 
Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.
Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS, Stratakis CA
Nature genetics. 2000 ; 26 (1) : 89-92.
PMID 10973256
 
Perspective: lessons learned from molecular genetic studies of thyroid cancer--insights into pathogenesis and tumor-specific therapeutic targets.
Fagin JA
Endocrinology. 2002 ; 143 (6) : 2025-2028.
PMID 12021165
 
Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD.
Groussin L, Kirschner LS, Vincent-Dejean C, Perlemoine K, Jullian E, Delemer B, Zacharieva S, Pignatelli D, Carney JA, Luton JP, Bertagna X, Stratakis CA, Bertherat J
American journal of human genetics. 2002 ; 71 (6) : 1433-1442.
PMID 12424709
 
High prevalence of RET proto-oncogene activation (RET/PTC) in papillary thyroid carcinomas.
Lam KY, Lo CY, Leung PS
European journal of endocrinology / European Federation of Endocrine Societies. 2002 ; 147 (6) : 741-745.
PMID 12457448
 
Genetic testing and genetic counselling in hypertrophic cardiomyopathy: the French experience.
Charron P, Hˆ©ron D, Gargiulo M, Richard P, Dubourg O, Desnos M, Bouhour JB, Feingold J, Carrier L, Hainque B, Schwartz K, Komajda M
Journal of medical genetics. 2002 ; 39 (10) : 741-746.
PMID 12362031
 
Regulatory subunit type I-alpha of protein kinase A (PRKAR1A): a tumor-suppressor gene for sporadic thyroid cancer.
Sandrini F, Matyakhina L, Sarlis NJ, Kirschner LS, Farmakidis C, Gimm O, Stratakis CA
Genes, chromosomes & cancer. 2002 ; 35 (2) : 182-192.
PMID 12203783
 
Molecular mechanisms of RET activation in human cancer.
Santoro M, Melillo RM, Carlomagno F, Fusco A, Vecchio G
Annals of the New York Academy of Sciences. 2002 ; 963 : 116-121.
PMID 12095936
 
Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity.
Bertherat J, Groussin L, Sandrini F, Matyakhina L, Bei T, Stergiopoulos S, Papageorgiou T, Bourdeau I, Kirschner LS, Vincent-Dejean C, Perlemoine K, Gicquel C, Bertagna X, Stratakis CA
Cancer research. 2003 ; 63 (17) : 5308-5319.
PMID 14500362
 
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Contributor(s)

Written10-2004Constantine A Stratakis, Ludmila Matyakhina

Citation

This paper should be referenced as such :
Stratakis, CA ; Matyakhina, L
PRKAR1A (protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1))
Atlas Genet Cytogenet Oncol Haematol. 2004;8(4):310-313.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/PRKAR1AID387.html

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