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PPP1R1B (protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine and cAMP regulated phosphoprotein, DARPP-32))

Written2007-12Wael El-Rifai, Abbes Belkhiri
Department of Surgery, Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee

(Note : for Links provided by Atlas : click)

Identity

Alias_namesprotein phosphatase 1
Alias_symbol (synonym)DARPP-32
FLJ20940
Other aliasDARPP32
t-DARPP
HGNC (Hugo) PPP1R1B
LocusID (NCBI) 84152
Atlas_Id 44096
Location 17q12  [Link to chromosome band 17q12]
Location_base_pair Starts at 37784751 and ends at 37792878 bp from pter ( according to hg19-Feb_2009)  [Mapping PPP1R1B.png]
 
  Genomic localization of DARPP-32, with FISH using BAC clone CTD-2019C10 (Research Genetics) that contains DARPP-32, using fluorescent in situ hybridization (FISH) on a normal metaphase spread. Arrows indicate the green FITC hybridization signals. The ideogram of chromosome 17 together with the inverted DAPI banding and FISH hybridization signals on the two chromosome 17. The FISH signals localize to chromosome band 17q12-q21.
Fusion genes
(updated 2016)
ERBB2 (17q12) / PPP1R1B (17q12)GALNT18 (11p15.3) / PPP1R1B (17q12)LASP1 (17q12) / PPP1R1B (17q12)
NLK (17q11.2) / PPP1R1B (17q12)PPP1R1B (17q12) / DDR1 (6p21.33)PPP1R1B (17q12) / PIPOX (17q11.2)
PPP1R1B (17q12) / RAB12 (18p11.22)SIK3 (11q23.3) / PPP1R1B (17q12)ZNHIT1 (7q22.1) / PPP1R1B (17q12)

DNA/RNA

 
  This schematic illustration shows the genomic structure of DARPP-32 and its transcriptional splice variant that encodes a truncated DARPP-32 protein (t-DARPP). The sequence length of the mRNA of DARPP-32 is 1,841 bp, including the untranslated 3' and 5' ends. The length of the transcriptional splice variant of DARPP-32 that encodes a truncated DARPP-32 protein (t-DARPP) is 1,502 bp. DARPP-32 and t-DARPP share an identical sequence from exon 2 to the 3' end. Each of them has seven exons. Each of DARPP-32 and t-DARPP transcripts has its own unique exon 1, where exon1 in DARPP-32 includes 548 bp whereas exon1 in t-DARPP consists of unique 207 bp that does not match with exon1 of DARPP-32.
Description DARPP-32 gene is located at 17q12. Both full length DARPP-32 and its transcriptional splice variant (t-DARPP) consist of seven exons where only exon 1 is unique in each of the two transcripts.
Transcription 2 alternative transcripts
Pseudogene Unknown

Protein

Description DARPP-32 encodes a protein of 204 amino acids (about 32 kD), whereas t-DARPP encodes a 168 amino acid protein (about 28 kD). DARPP-32 contains four phosphorylation sites at Thr34, Thr75, Ser102, and Ser137, whereas t-DARPP lacks the Thr34 phosphorylation site of DARPP-32. The schematic illustration, shown above, demonstrates the phosphorylation sites of DARPP-32 and t-DARPP shown in yellow color.
Expression DARPP-32 protein is highly expressed in medium-sized spiny neurons of the neostriatum. DARPP-32 was characterized as a major target for dopamine and protein kinase A signaling. Modulation of DARPP-32 phosphorylation state provides a molecular mechanism for integrating signals through several neurotransmitters and steroid hormones that stimulate dopaminoceptic neurons in various regions of the brain. Activation of PKA or PKG leads to phosphorylation of DARPP-32 at Thr34 and subsequently converts DARPP-32 into a potent inhibitor of protein phosphatase-1 (PP-1). Cdk5 can also phosphorylate DARPP-32 at Thr75 and this converts DARPP-32 into a PKA inhibitor. Expression of t-DARPP in the brain was not reported.
Protein and mRNA expression of both DARPP-32 and t-DARPP are expressed at varying levels in several types of normal epithelial tissues outside the brain. DARPP-32 and t-DARPP are over-expressed in carcinomas of the breast, prostate, colon, and stomach compared with normal tissue samples. The observation that DARPP-32 and t-DARPP are frequently over-expressed in common subtypes of human cancers suggests that these proteins may play a role in tumorigenesis. The expression of t-DARPP has been shown to increase the AKT kinase activity and regulate the levels of BCL2 in cancer cells. This effect is believed to mediate resistance to drug-induced apoptosis.
Localisation Cytosolic
Homology Unknown

Mutations

Note Unknown

Implicated in

Note
  
Entity Dopaminergic disorders
Disease DARPP-32 plays a key role in cognitive function, and multiple brain functions. DARPP-32 is a key mediator of the biochemical, electrophysiological, transcriptional, and behavioral effects of dopamine. In this respect, DARPP-32 plays a critical role in dopaminoceptive neurons in the neostriatum (and likely in other brain regions) in signal transduction pathways regulated by a variety of neurotransmitters, neuromodulators, and neuropeptides. Abnormal signaling through DARPP-32 has been implicated in several major neurologic and psychiatric disorders. DARPP-32 may be involved in the pathogenesis of schizophrenia and plays a role in mediating the actions of a broad range of drugs of abuse.
  
  
Entity Cancers
Oncogenesis Over-expression of DARPP-32 and t-DARPP are associated with gastric cancer, and confer a potent anti-apoptotic function in cancer cells through a p53-independent mechanism that involves preservation of mitochondrial membrane potential and increased Bcl2 expression levels. t-DARPP transcriptionally up-regulates Bcl2 by an Akt-dependent mechanism through activation of CREB/ATF-1 transcription factors in gastric cancer. DARPP-32 is frequently over-expressed in multiple human adenocarcinomas suggesting that DARPP-32 proteins may be important in tumorigenesis. Decreased expression of DARPP-32, however, in oral premalignant and malignant lesions was observed, and thereby suggested that DARPP-32 may be a tumor suppressor in this particular malignancy. In addition, phosphorylation of DARPP-32 at Thr34 or Thr75 appears to regulate breast cancer cell migration downstream of the receptor tyrosine kinase DDR1.
  

Bibliography

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t-Darpp promotes cancer cell survival by up-regulation of Bcl2 through Akt-dependent mechanism.
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Gastric cancers overexpress DARPP-32 and a novel isoform, t-DARPP.
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PMID 12124342
 
DARPP-32: regulator of the efficacy of dopaminergic neurotransmission.
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DARPP-32 (dopamine and 3',5'-cyclic adenosine monophosphate-regulated neuronal phosphoprotein) is essential for the maintenance of thyroid differentiation.
García-Jimé C, Zaballos MA, Santisteban P
Molecular endocrinology (Baltimore, Md.). 2005 ; 19 (12) : 3060-3072.
PMID 16020482
 
Neuronal phosphoproteins. Mediators of signal transduction.
Greengard P
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PMID 2908293
 
Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade.
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PMID 10433257
 
Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices.
Halpain S, Girault JA, Greengard P
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PMID 2153935
 
DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1.
Hemmings HC Jr, Greengard P, Tung HY, Cohen P
Nature. 1984 ; 310 (5977) : 503-505.
PMID 6087160
 
Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine.
Lindskog M, Svenningsson P, Pozzi L, Kim Y, Fienberg AA, Bibb JA, Fredholm BB, Nairn AC, Greengard P, Fisone G
Nature. 2002 ; 418 (6899) : 774-778.
PMID 12181566
 
Requirement for DARPP-32 in progesterone-facilitated sexual receptivity in female rats and mice.
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Functional dopamine-1 receptors and DARPP-32 are expressed in human ovary and granulosa luteal cells in vitro.
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Citation

This paper should be referenced as such :
El-Rifai, W ; Belkhiri, A
PPP1R1B (protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine, cAMP regulated phosphoprotein, DARPP-32))
Atlas Genet Cytogenet Oncol Haematol. 2008;12(4):325-327.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PPP1R1BID44096ch17q12.html


External links

Nomenclature
HGNC (Hugo)PPP1R1B   9287
Cards
AtlasPPP1R1BID44096ch17q12
Entrez_Gene (NCBI)PPP1R1B  84152  protein phosphatase 1 regulatory inhibitor subunit 1B
AliasesDARPP-32; DARPP32
GeneCards (Weizmann)PPP1R1B
Ensembl hg19 (Hinxton)ENSG00000131771 [Gene_View]  chr17:37784751-37792878 [Contig_View]  PPP1R1B [Vega]
Ensembl hg38 (Hinxton)ENSG00000131771 [Gene_View]  chr17:37784751-37792878 [Contig_View]  PPP1R1B [Vega]
ICGC DataPortalENSG00000131771
TCGA cBioPortalPPP1R1B
AceView (NCBI)PPP1R1B
Genatlas (Paris)PPP1R1B
WikiGenes84152
SOURCE (Princeton)PPP1R1B
Genetics Home Reference (NIH)PPP1R1B
Genomic and cartography
GoldenPath hg19 (UCSC)PPP1R1B  -     chr17:37784751-37792878 +  17q12   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)PPP1R1B  -     17q12   [Description]    (hg38-Dec_2013)
EnsemblPPP1R1B - 17q12 [CytoView hg19]  PPP1R1B - 17q12 [CytoView hg38]
Mapping of homologs : NCBIPPP1R1B [Mapview hg19]  PPP1R1B [Mapview hg38]
OMIM604399   
Gene and transcription
Genbank (Entrez)AF233349 AF435972 AF435973 AF435974 AF464196
RefSeq transcript (Entrez)NM_001242464 NM_032192 NM_181505
RefSeq genomic (Entrez)NC_000017 NC_018928 NG_030330 NT_010783 NW_004929407
Consensus coding sequences : CCDS (NCBI)PPP1R1B
Cluster EST : UnigeneHs.286192 [ NCBI ]
CGAP (NCI)Hs.286192
Alternative Splicing GalleryENSG00000131771
Gene ExpressionPPP1R1B [ NCBI-GEO ]   PPP1R1B [ EBI - ARRAY_EXPRESS ]   PPP1R1B [ SEEK ]   PPP1R1B [ MEM ]
Gene Expression Viewer (FireBrowse)PPP1R1B [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)84152
GTEX Portal (Tissue expression)PPP1R1B
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UD71   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9UD71  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9UD71
Splice isoforms : SwissVarQ9UD71
PhosPhoSitePlusQ9UD71
Domains : Interpro (EBI)Dopamine/cAMP_neuron_P-prot    PPI_1DARPP-32   
Domain families : Pfam (Sanger)DARPP-32 (PF05395)   
Domain families : Pfam (NCBI)pfam05395   
Conserved Domain (NCBI)PPP1R1B
DMDM Disease mutations84152
Blocks (Seattle)PPP1R1B
SuperfamilyQ9UD71
Human Protein AtlasENSG00000131771
Peptide AtlasQ9UD71
HPRD05097
IPIIPI00003363   IPI00220698   IPI00795211   
Protein Interaction databases
DIP (DOE-UCLA)Q9UD71
IntAct (EBI)Q9UD71
FunCoupENSG00000131771
BioGRIDPPP1R1B
STRING (EMBL)PPP1R1B
ZODIACPPP1R1B
Ontologies - Pathways
QuickGOQ9UD71
Ontology : AmiGOresponse to amphetamine  protein kinase inhibitor activity  cAMP-dependent protein kinase inhibitor activity  protein phosphatase inhibitor activity  protein serine/threonine phosphatase inhibitor activity  protein binding  nucleus  cytoplasm  cytosol  transcription, DNA-templated  negative regulation of protein kinase activity  signal transduction  negative regulation of female receptivity  visual learning  protein phosphatase type 1 regulator activity  D1 dopamine receptor binding  D2 dopamine receptor binding  D3 dopamine receptor binding  D4 dopamine receptor binding  D5 dopamine receptor binding  intracellular signal transduction  neuronal cell body  negative regulation of catalytic activity  negative regulation of catalytic activity  regulation of catalytic activity  negative regulation of protein serine/threonine kinase activity  
Ontology : EGO-EBIresponse to amphetamine  protein kinase inhibitor activity  cAMP-dependent protein kinase inhibitor activity  protein phosphatase inhibitor activity  protein serine/threonine phosphatase inhibitor activity  protein binding  nucleus  cytoplasm  cytosol  transcription, DNA-templated  negative regulation of protein kinase activity  signal transduction  negative regulation of female receptivity  visual learning  protein phosphatase type 1 regulator activity  D1 dopamine receptor binding  D2 dopamine receptor binding  D3 dopamine receptor binding  D4 dopamine receptor binding  D5 dopamine receptor binding  intracellular signal transduction  neuronal cell body  negative regulation of catalytic activity  negative regulation of catalytic activity  regulation of catalytic activity  negative regulation of protein serine/threonine kinase activity  
Pathways : BIOCARTAFOSB gene expression and drug abuse [Genes]    Regulation of ck1/cdk5 by type 1 glutamate receptors [Genes]   
Pathways : KEGGDopaminergic synapse    Cocaine addiction    Amphetamine addiction    Alcoholism   
REACTOMEQ9UD71 [protein]
REACTOME Pathways180024 [pathway]   
NDEx NetworkPPP1R1B
Atlas of Cancer Signalling NetworkPPP1R1B
Wikipedia pathwaysPPP1R1B
Orthology - Evolution
OrthoDB84152
GeneTree (enSembl)ENSG00000131771
Phylogenetic Trees/Animal Genes : TreeFamPPP1R1B
HOVERGENQ9UD71
HOGENOMQ9UD71
Homologs : HomoloGenePPP1R1B
Homology/Alignments : Family Browser (UCSC)PPP1R1B
Gene fusions - Rearrangements
Fusion : MitelmanGALNT18/PPP1R1B [11p15.3/17q12]  [t(11;17)(p15;q12)]  
Fusion : MitelmanPPP1R1B/PIPOX [17q12/17q11.2]  [t(17;17)(q11;q12)]  
Fusion : MitelmanSIK3/PPP1R1B [11q23.3/17q12]  [t(11;17)(q23;q12)]  
Fusion : MitelmanZNHIT1/PPP1R1B [7q22.1/17q12]  [t(7;17)(q22;q12)]  
Fusion: TCGAERBB2 17q12 PPP1R1B 17q12 BLCA
Fusion: TCGAGALNTL4 PPP1R1B 17q12 BRCA
Fusion: TCGASIK3 11q23.3 PPP1R1B 17q12 BRCA
Fusion: TCGAZNHIT1 7q22.1 PPP1R1B 17q12 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPPP1R1B [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PPP1R1B
dbVarPPP1R1B
ClinVarPPP1R1B
1000_GenomesPPP1R1B 
Exome Variant ServerPPP1R1B
ExAC (Exome Aggregation Consortium)PPP1R1B (select the gene name)
Genetic variants : HAPMAP84152
Genomic Variants (DGV)PPP1R1B [DGVbeta]
DECIPHER (Syndromes)17:37784751-37792878  ENSG00000131771
CONAN: Copy Number AnalysisPPP1R1B 
Mutations
ICGC Data PortalPPP1R1B 
TCGA Data PortalPPP1R1B 
Broad Tumor PortalPPP1R1B
OASIS PortalPPP1R1B [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPPP1R1B  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPPP1R1B
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PPP1R1B
DgiDB (Drug Gene Interaction Database)PPP1R1B
DoCM (Curated mutations)PPP1R1B (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PPP1R1B (select a term)
intoGenPPP1R1B
NCG5 (London)PPP1R1B
Cancer3DPPP1R1B(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM604399   
Orphanet
MedgenPPP1R1B
Genetic Testing Registry PPP1R1B
NextProtQ9UD71 [Medical]
TSGene84152
GENETestsPPP1R1B
Huge Navigator PPP1R1B [HugePedia]
snp3D : Map Gene to Disease84152
BioCentury BCIQPPP1R1B
ClinGenPPP1R1B
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD84152
Chemical/Pharm GKB GenePA33639
Clinical trialPPP1R1B
Miscellaneous
canSAR (ICR)PPP1R1B (select the gene name)
Probes
Litterature
PubMed89 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePPP1R1B
EVEXPPP1R1B
GoPubMedPPP1R1B
iHOPPPP1R1B
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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