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PHLPP1 (PH domain leucine-rich repeat protein phosphatase 1)

Written2009-06Audrey K O'Neill, Alexandra C Newton
Department of Pharmacology, University of California San Diego, 9500 Gilman Dr., 0721, La Jolla, CA 92093, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesMg2?? dependent 3A
PLEKHE1
PHLPP
Alias_symbol (synonym)KIAA0606
SCOP
PPM3A
Other aliasMGC161555
HGNC (Hugo) PHLPP1
LocusID (NCBI) 23239
Atlas_Id 44544
Location 18q21.33  [Link to chromosome band 18q21]
Location_base_pair Starts at 62715439 and ends at 62980443 bp from pter ( according to hg19-Feb_2009)  [Mapping PHLPP1.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ADGRD1 (12q24.33) / PHLPP1 (18q21.33)PHLPP1 (18q21.33) / WDR12 (2q33.2)ZNF626 (19p12) / PHLPP1 (18q21.33)

DNA/RNA

 
  Genomic organization of the PHLPP1alpha and PHLPP1beta transcripts. Exons are represented by blue (PHLPP1alpha) or red (PHLPP1beta) boxes, and position along chromosome 18 is indicated by the scale bar at the top.
Description The gene for PHLPP1 is located at 18q21.33. It encompasses two different splice variants: PHLPP1alpha and PHLPP1beta. PHLPP1alpha spans 154 kb and includes 16 exons. The PHLPP1beta gene is identical to the PHLPP1alpha gene except that it has a much (~1.5 kb) longer exon 1 and a slightly shorter exon 2. Including the new exon 1, the PHLPP1beta gene is 265 kb in length. PHLPP1 is one of two separate genes in the PHLPP gene family; the second gene, PHLPP2, is located at 16q22.3.
Transcription The PHLPP1alpha and PHLPP1beta transcripts are identical except for exon 1 and the beginning of exon 2. The PHLPP1alpha transcript is 4617 bp; the PHLPP1beta transcript is 6155 bp.

Protein

 
  PHLPP1alpha and PHLPP1beta protein structure.
Description The PHLPP1alpha and PHLPP1beta proteins both contain a pleckstrin homology (PH) domain, a series of leucine-rich repeats (LRR), a PP2C phosphatase domain, and a C-terminal PDZ (post synaptic density protein [PSD95], Drosophila disc large tumor suppressor [DlgA], and zonula occludens-1 protein [zo-1]) binding motif. In addition, PHLPP1beta has a putative Ras association (RA) domain near its N-terminus. PHLPP1alpha is composed of 1205 amino acids and has a molecular weight of approximately 133 kDa, while PHLPP1beta has 1717 amino acids and a molecular weight of approximately 185 kDa. (The related isoform PHLPP2 has a domain structure similar to that of PHLPP1beta).
Expression PHLPP1 is expressed in most human cancer cell lines and all mouse tissues examined so far. PHLPP1beta appears to be more abundant than PHLPP1alpha. Rat PHLPP1beta (termed SCOP for Suprachiasmatic nucleus circadian oscillatory protein) is also expressed in the suprachiasmatic nucleus, where its mRNA expression oscillates in a circadian fashion.
Localisation PHLPP1 appears to be localized throughout the cell.
Function PHLPP1 is a phosphatase that specifically dephosphorylates the hydrophobic motif (HM) of Akt and conventional/novel PKC isoforms. HM phosphorylation is important for the function of both kinases. For Akt, phosphorylation at serine 473, the HM site, allows full activation of the kinase and subsequent phosphorylation of its downstream substrates. For PKC, phosphorylation of the HM (serine 660 in PKCbetaII) increases protein stability; once the HM is dephosphorylated, two other important regulatory sites on the kinase (the activation loop and the turn motif) are rendered more sensitive to dephosphorylation by other phosphatases. The dephosphorylated PKC is then shunted to the detergent-insoluble fraction of the cell, where it is degraded. PHLPP1 therefore functions to decrease the activity of both Akt and PKC, albeit by different mechanisms.

While PHLPP1 and its family member PHLPP2 have similar functions, their specificity for Akt isoforms differs. PHLPP1 preferentially binds and dephosphorylates Akt2 and Akt3, resulting in decreased phosphorylation of a set of Akt targets that includes GSK-3beta, TSC2, and FoxO, as well as and GSK3a. PHLPP2, on the other hand, binds and dephosphorylates Akt1 and Akt3, resulting in downregulation of an overlapping yet distinct set of downstream targets: GSK-3beta, TSC2, and FoxO, as well as TSC2 and p27.

Interestingly, PHLPP1's regulation of its protein substrates appears to be regulated by its protein-protein interaction domains. PHLPP1 lacking a C-terminal PDZ ligand is unable to dephosphorylate Akt, whereas deletion of PHLPP1's PH domain decreases its ability to dephosphorylate PKC.

Since PHLPP1 downregulates the pro-survival kinase Akt, it is not surprising that this phosphatase plays roles in apoptosis and suppression of cellular proliferation. siRNA-mediated reduction of PHLPP1 causes increased apoptosis in a number of cell lines, whereas overexpression of PHLPP1 decreases proliferation in LN229, a glioblastoma cell line, and suppresses its ability to form tumors in nude mice.

PHLPP1 also regulates the phosphorylation and activity of ERK; it has been suggested to interact directly with the nucleotide-free form of K-Ras and thus suppress the Ras/Raf/MEK/ERK pathway. This pathway is important for the regulation of learning and memory, and overexpression of rat PHLPP1beta in the hippocampus of transgenic mice abolishes memory for novel objects. In addition, training for hippocampus-based learning prompts calpain protease-mediated degradation of PHLPP1. Together, these results suggest that proper regulation of PHLPP1 in certain neurons is crucial for memory formation.

Homology PHLPP is a highly conserved phosphatase; its earliest orthologue is the yeast protein CYR1. In addition to a PP2C phosphatase domain, a leucine-rich repeat, and a Ras association domain, CYR1 contains an adenylate cyclase domain near its C terminus. Though invertebrates have only one PHLPP gene, most vertebrates have genes for both PHLPP1 and PHLPP2.

Mutations

Somatic One glioblastoma multiforme sample was found to have a mutation in the catalytic domain of PHLPP1 (M738T in the PHLPP1a transcript). This tumor sample presented with mutations in several other known tumor suppressors, including PTEN and Rb.

Implicated in

Note
  
Entity Glioblastoma multiforme
Oncogenesis PHLPP1 overexpression in human LN229 cells limits their ability to form tumors in a xenograft model. Various human glioblastoma cell lines respond to PHLPP1 knockdown with increased Akt phosphorylation. In addition, mRNA expression of both PHLPP1 and PHLPP2 are decreased by around 30% in patient glioblastoma samples (relative to normal brain).
  
  
Entity Colorectal cancer
Cytogenetics 18q21.33, the chromosomal locus containing the gene for PHLPP1 as well as the putative tumor suppressors BCL2 and Maspin, commonly undergoes loss of heterozygosity in colon cancers.
Oncogenesis Overexpression of PHLPP1 or PHLPP2 in the human colon cancer cell lines HCT-116 and HT29 causes decreased expression of PKC and decreased phosphorylation of Akt. Cells overexpressing PHLPP exhibit decreased proliferation and were less able to induce tumors in nude mice. Conversely, DLD1 cells, which express high levels of PHLPP, respond to PHLPP1 or PHLPP2 knockdown with increased Akt phosphorylation, PKC stability, and proliferation.
  
  
Entity Leukemia
Disease Chronic lymphocytic leukemia, chronic myelogenous leukemia
Oncogenesis PHLPP1 mRNA expression is frequently reduced to undetectable levels in patients with chronic lymphocytic leukemia (CLL). About 50% of CLL patients have loss of chromosomal region 13q14, and about 50% of these show drastically reduced PHLPP1 expression. In chronic myelogenous leukemia (CML), PHLPP mRNA levels may also be decreased, albeit by a different mechanism. Bcr-Abl, the fusion protein responsible for CML, downregulates PHLPP1 and PHLPP2 mRNA levels; decreasing PHLPP levels interferes with the efficacy of Bcr-Abl inihibitors, including Gleevec, in CML cell lines.
  

Bibliography

PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms.
Brognard J, Sierecki E, Gao T, Newton AC.
Mol Cell. 2007 Mar 23;25(6):917-31.
PMID 17386267
 
PHLiPPing the switch on Akt and protein kinase C signaling.
Brognard, J, Newton AC.
Trends Endocrinol Metab 2008 Aug;19(6):223-30. (REVIEW)
PMID 18511290
 
Comprehensive genomic characterization defines human glioblastoma genes and core pathways.
Cancer Genome Atlas Research Network.
Nature. 2008 Oct 23;455(7216):1061-8.
PMID 18772890
 
The phosphatase PHLPP controls the cellular levels of protein kinase C.
Gao T, Brognard J, Newton AC.
J Biol Chem. 2008 Mar 7;283(10):6300-11.
PMID 18162466
 
PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth.
Gao T, Furnari F, Newton AC.
Mol Cell. 2005 Apr 1;18(1):13-24.
PMID 15808505
 
Depletion of pleckstrin homology domain leucine-rich repeat protein phosphatase 1 and 2 by Bcr-Abl promotes chronic myelogenous leukemia cell proliferation through continuous phosphorylation of Akt isoforms.
Hirano I, Nakamura S, Yokota D, Ono T, Shigeno K, Fujisawa S, Shinjo K, Ohnishi K.
J Biol Chem. 2009 Mar 4. [Epub ahead of print]
PMID 19261608
 
Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis.
Liu J, Weiss HL, Rychahou P, Jackson LN, Evers BM, Gao T.
Oncogene. 2009 Feb 19;28(7):994-1004.
PMID 19079341
 
PHLPPing it off: phosphatases get in the Akt.
Mendoza MC, Blenis J.
Mol Cell. 2007 Mar 23;25(6):798-800. (REVIEW)
PMID 17386258
 
Integrated genomic profiling of chronic lymphocytic leukemia identifies subtypes of deletion 13q14.
Ouillette P, Erba H, Kujawski L, Kaminski M, Shedden K, Malek SN.
Cancer Res. 2008 Feb 15;68(4):1012-21.
PMID 18281475
 
Suprachiasmatic nucleus circadian oscillatory protein, a novel binding partner of K-Ras in the membrane rafts, negatively regulates MAPK pathway.
Shimizu K, Okada M, Nagai K, Fukada Y.
J Biol Chem. 2003 Apr 25;278(17):14920-5. Epub 2003 Feb 19.
PMID 12594205
 
Proteolytic degradation of SCOP in the hippocampus contributes to activation of MAP kinase and memory.
Shimizu K, Phan T, Mansuy IM, Storm DR.
Cell. 2007 Mar 23;128(6):1219-29.
PMID 17382888
 
Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain.
Sun L, Hui AM, Su Q, Vortmeyer A, Kotliarov Y, Pastorino S, Passaniti A, Menon J, Walling J, Bailey R, Rosenblum M, Mikkelsen T, Fine HA.
Cancer Cell. 2006 Apr;9(4):287-300.
PMID 16616334
 

Citation

This paper should be referenced as such :
O'Neill, AK ; Newton, AC
PHLPP1 (PH domain leucine-rich repeat protein phosphatase 1)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(5):464-466.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PHLPP1ID44544ch18q21.html


External links

Nomenclature
HGNC (Hugo)PHLPP1   20610
Cards
AtlasPHLPP1ID44544ch18q21
Entrez_Gene (NCBI)PHLPP1  23239  PH domain and leucine rich repeat protein phosphatase 1
AliasesPHLPP; PLEKHE1; PPM3A; SCOP
GeneCards (Weizmann)PHLPP1
Ensembl hg19 (Hinxton)ENSG00000081913 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000081913 [Gene_View]  chr18:62715439-62980443 [Contig_View]  PHLPP1 [Vega]
ICGC DataPortalENSG00000081913
TCGA cBioPortalPHLPP1
AceView (NCBI)PHLPP1
Genatlas (Paris)PHLPP1
WikiGenes23239
SOURCE (Princeton)PHLPP1
Genetics Home Reference (NIH)PHLPP1
Genomic and cartography
GoldenPath hg38 (UCSC)PHLPP1  -     chr18:62715439-62980443 +  18q21.33   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PHLPP1  -     18q21.33   [Description]    (hg19-Feb_2009)
EnsemblPHLPP1 - 18q21.33 [CytoView hg19]  PHLPP1 - 18q21.33 [CytoView hg38]
Mapping of homologs : NCBIPHLPP1 [Mapview hg19]  PHLPP1 [Mapview hg38]
OMIM609396   
Gene and transcription
Genbank (Entrez)AB011178 AF130097 AK001924 AK124714 AL079409
RefSeq transcript (Entrez)NM_194449
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)PHLPP1
Cluster EST : UnigeneHs.465337 [ NCBI ]
CGAP (NCI)Hs.465337
Alternative Splicing GalleryENSG00000081913
Gene ExpressionPHLPP1 [ NCBI-GEO ]   PHLPP1 [ EBI - ARRAY_EXPRESS ]   PHLPP1 [ SEEK ]   PHLPP1 [ MEM ]
Gene Expression Viewer (FireBrowse)PHLPP1 [ Firebrowse - Broad ]
|a hrEf=/./extdef.html#SOURCE TARGET=SOURCE>SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)23239
GTEX Portal (Tissue expression)PHLPP1
Human Protein AtlasENSG00000081913-PHLPP1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO60346   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO60346  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO60346
Splice isoforms : SwissVarO60346
Catalytic activity : Enzyme3.1.3.16 [ Enzyme-Expasy ]   3.1.3.163.1.3.16 [ IntEnz-EBI ]   3.1.3.16 [ BRENDA ]   3.1.3.16 [ KEGG ]   
PhosPhoSitePlusO60346
Domaine pattern : Prosite (Expaxy)LRR (PS51450)    PH_DOMAIN (PS50003)    PPM_2 (PS51746)   
Domains : Interpro (EBI)L_dom-like    Leu-rich_rpt    Leu-rich_rpt_typical-subtyp    PH_dom-like    PH_domain    PPM-type_phosphatase_dom   
Domain families : Pfam (Sanger)LRR_6 (PF13516)    LRR_8 (PF13855)    PH (PF00169)    PP2C (PF00481)   
Domain families : Pfam (NCBI)pfam13516    pfam13855    pfam00169    pfam00481   
Domain families : Smart (EMBL)LRR_TYP (SM00369)  PP2Cc (SM00332)  
Conserved Domain (NCBI)PHLPP1
DMDM Disease mutations23239
Blocks (Seattle)PHLPP1
SuperfamilyO60346
Human Protein Atlas [tissue]ENSG00000081913-PHLPP1 [tissue]
Peptide AtlasO60346
HPRD15145
IPIIPI00297617   IPI00017920   IPI00939319   IPI00980747   
Protein Interaction databases
DIP (DOE-UCLA)O60346
IntAct (EBI)O60346
FunCoupENSG00000081913
BioGRIDPHLPP1
STRING (EMBL)PHLPP1
ZODIACPHLPP1
Ontologies - Pathways
QuickGOO60346
Ontology : AmiGOregulation of T cell anergy  protein serine/threonine phosphatase activity  protein binding  cytoplasm  cytosol  plasma membrane  protein dephosphorylation  apoptotic process  entrainment of circadian clock  nuclear membrane  regulation of apoptotic process  regulation of MAPK cascade  regulation of JNK cascade  metal ion binding  negative regulation of protein kinase B signaling  regulation of protein kinase C signaling  regulation of p38MAPK cascade  
Ontology : EGO-EBIregulation of T cell anergy  protein serine/threonine phosphatase activity  protein binding  cytoplasm  cytosol  plasma membrane  protein dephosphorylation  apoptotic process  entrainment of circadian clock  nuclear membrane  regulation of apoptotic process  regulation of MAPK cascade  regulation of JNK cascade  metal ion binding  negative regulation of protein kinase B signaling  regulation of protein kinase C signaling  regulation of p38MAPK cascade  
Pathways : KEGGPI3K-Akt signaling pathway   
REACTOMEO60346 [protein]
REACTOME PathwaysR-HSA-199418 [pathway]   
NDEx NetworkPHLPP1
Atlas of Cancer Signalling NetworkPHLPP1
Wikipedia pathwaysPHLPP1
Orthology - Evolution
OrthoDB23239
GeneTree (enSembl)ENSG00000081913
Phylogenetic Trees/Animal Genes : TreeFamPHLPP1
HOVERGENO60346
HOGENOMO60346
Homologs : HomoloGenePHLPP1
Homology/Alignments : Family Browser (UCSC)PHLPP1
Gene fusions - Rearrangements
Fusion : MitelmanPHLPP1/WDR12 [18q21.33/2q33.2]  
Fusion: TCGA_MDACCPHLPP1 18q21.33 WDR12 2q33.2 LUSC
Tumor Fusion PortalPHLPP1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPHLPP1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PHLPP1
dbVarPHLPP1
ClinVarPHLPP1
1000_GenomesPHLPP1 
Exome Variant ServerPHLPP1
ExAC (Exome Aggregation Consortium)ENSG00000081913
GNOMAD BrowserENSG00000081913
Genetic variants : HAPMAP23239
Genomic Variants (DGV)PHLPP1 [DGVbeta]
DECIPHERPHLPP1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPHLPP1 
Mutations
ICGC Data PortalPHLPP1 
TCGA Data PortalPHLPP1 
Broad Tumor PortalPHLPP1
OASIS PortalPHLPP1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPHLPP1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPHLPP1
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 PHLPP1
DgiDB (Drug Gene Interaction Database)PHLPP1
DoCM (Curated mutations)PHLPP1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PHLPP1 (select a term)
intoGenPHLPP1
NCG5 (London)PHLPP1
Cancer3DPHLPP1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM609396   
Orphanet
DisGeNETPHLPP1
MedgenPHLPP1
Genetic Testing Registry PHLPP1
NextProtO60346 [Medical]
TSGene23239
GENETestsPHLPP1
Target ValidationPHLPP1
Huge Navigator PHLPP1 [HugePedia]
snp3D : Map Gene to Disease23239
BioCentury BCIQPHLPP1
ClinGenPHLPP1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD23239
Chemical/Pharm GKB GenePA165429055
Clinical trialPHLPP1
Miscellaneous
canSAR (ICR)PHLPP1 (select the gene name)
Probes
Litterature
PubMed68 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePHLPP1
EVEXPHLPP1
GoPubMedPHLPP1
iHOPPHLPP1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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