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PHLPP2 (PH domain leucine-rich repeat protein phosphatase 2)

Identity

Other namesPHLPPL
KIAA0931
HGNC (Hugo) PHLPP2
LocusID (NCBI) 23035
Location 16q22.2
Location_base_pair Starts at 71678829 and ends at 71749743 bp from pter ( according to hg19-Feb_2009)

DNA/RNA

 
  Genomic organization of the PHLPP2 transcripts. Exons are represented by boxes, and position along chromosome 16 is indicated by the scale bar at the top.
Description The gene for PHLPP2 is located at 16q22.3 and spans approximately 70 kb. The most recent version of the Ensembl database predicts four splice variants of PHLPP2, whose sizes range from 69.8 to 73.9 kb (see diagram).
Transcription The predicted PHLPP2 transcripts have between 2877 and 7919 bp. Three of these predicted variants have 18 exons; the 7718 bp variant has only 17 exons. All of the variants have similar exon structures; only exon 1 and exon 7 (which is missing in the 7718 bp variant) differ. Of these putative transcripts, only the largest of these transcripts (labeled "PHLPP2" in the diagram) has been cloned and characterized.

Protein

 
  PHLPP2 protein structure.
Description Like the related isoform PHLPP1beta, the PHLPP2 protein contains a Ras association (RA) domain, 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. The characterized PHLPP1 protein has 1323 amino acids and a predicted molecular weight of approximately 147 kDa. Of the uncharacterized shorter transcripts, the longer (1256 aa) variant has a similar structure, while the two shorter variants (792 and 956 amino acids respectively) lack the RA and PH domains.
Expression PHLPP2 is expressed in many human cancer cell lines and in all mouse tissues examined so far.
Localisation PHLPP2 appears to be predominantly expressed in the cytosolic and nuclear fractions.
Function PHLPP2, like PHLPP1, dephosphorylates Akt and conventional/novel protein kinase C (PKC) isoforms at their hydrophobic motifs (HM). Both kinases are regulated by phosphorylation at this site, which corresponds to serine 473 in Akt1 and serine 660 in PKCbetaII. HM motif phosphorylation of Akt occurs under agonist-stimulated conditions and allows full activation of the kinase. Phosphorylation of PKC's HM motif, on the other hand, is constitutive and regulates PKC stability. HM dephosphorylation by PHLPP renders PKC susceptible to dephosphorylation at two other important regulatory sites on the kinase (the activation loop and the turn motif). The fully-dephosphorylated form of PKC is shunted to the detergent-insoluble pellet and degraded. Thus, PHLPP functions to decrease Akt's activity and PKC's stability, effectively dowregulating both kinases.

While PHLPP2 and its family member PHLPP1 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 HDM2 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.

PHLPP2 regulates cellular survival and proliferation, partially by regulating Akt. PHLPP2 overexpression increases apoptosis in cancer cell lines under low serum conditions; this effect is partially blocked by overexpressing an Akt mutant that is resistant to dephosphorylation by PHLPP. Conversely, siRNA-mediated knockdown of PHLPP2 decreases basal and etoposide-stimulated apoptosis and increases cellular proliferation.

PHLPP2 may also be involved in cAMP signaling to Akt. PHLPP2 binds adenylyl cyclase type 6 in cardiac myocytes, and treatments that raise cAMP levels decrease Akt HM phosphorylation, possibly through activation of PHLPP.

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 A common single nucleotide polymorphism (SNP) in the PP2C phosphatase domain of PHLPP2 may be involved in breast cancer progression. This SNP, a T->C nucleotide change at base pair position 3047, results in a Leu->Ser amino acid change at position 1016 in the PHLPP2 protein. Heterozygosity at this position is present in approximately 30% of the population, although Ser/Ser homozygosity has not yet been observed.

The L1016S variant of PHLPP2 may be involved in breast cancer. Although most breast cancer cell lines are homozygous for the Leucine allele, some are homozygous for the Serine allele. In addition, the normal breast cell line Hs578Bst is heterozygous (Leu/Ser) at position 1016, while its pair-matched tumor cell line Hs578t has only the Serine allele, suggesting that the gene has undergone loss of heterozygosity in this tumor. Similar results were obtained upon comparing normal and tumor tissues from breast cancer patients who are heterozygous at position 1016. High-grade breast tumors from some of these patients exhibited loss of the Leucine allele, but no tumors exhibited loss of the Serine allele. Further characterization of the L1016S mutant has revealed that its phosphatase activity (as measured by activity toward Akt) and its ability to promote apoptosis are defective. Moreover, siRNA-mediated knockdown of PHLPP2 in Ser/Ser breast cancer cell lines has no effect on Akt phosphorylation or PKCalpha levels, while knocking down PHLPP2 in cell lines with at least one Leucine allele increases Akt phosphorylation and PKCalpha levels. All in all, the data indicate that the version of PHLPP2 with Serine at position 1016 is less functional towards Akt and PKC than the wildtype version, and that loss of the wildtype allele in heterozygous (Leu/Ser) breast cancer patients may be involved in the progression of breast cancer.

Implicated in

Entity Various cancer
Cytogenetics 16q22.3, the chromosomal locus containing PHLPP2, commonly undergoes loss of heterozygosity in breast and ovarian cancers, Wilms tumors, prostate cancer and hepatocellular carcinomas.
Oncogenesis siRNA-mediated reduction of PHLPP2 in breast cancer cell lines results in decreased apoptosis and increased proliferation, suggesting that PHLPP2 may act as a tumor suppressor. In addition, wildtype PHLPP2 may be lost in breast tumors with a less-functional PHLPP2 (PHLPP2 L1016S; see "Mutations" section), resulting in impaired Akt dephosphorylation and accelerating tumor development.
  
Entity Colorectal cancer
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 Chronic myelogenous leukemia
Oncogenesis PHLPP mRNA levels may be decreased in chronic myelogenous leukemia (CML). 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.
  

External links

Nomenclature
HGNC (Hugo)PHLPP2   29149
Cards
AtlasPHLPP2ID44546ch16q22
Entrez_Gene (NCBI)PHLPP2  23035  PH domain and leucine rich repeat protein phosphatase 2
GeneCards (Weizmann)PHLPP2
Ensembl (Hinxton)ENSG00000040199 [Gene_View]  chr16:71678829-71749743 [Contig_View]  PHLPP2 [Vega]
ICGC DataPortalENSG00000040199
cBioPortalPHLPP2
AceView (NCBI)PHLPP2
Genatlas (Paris)PHLPP2
WikiGenes23035
SOURCE (Princeton)NM_001289003 NM_015020
Genomic and cartography
GoldenPath (UCSC)PHLPP2  -  16q22.2   chr16:71678829-71749743 -  16q22.2   [Description]    (hg19-Feb_2009)
EnsemblPHLPP2 - 16q22.2 [CytoView]
Mapping of homologs : NCBIPHLPP2 [Mapview]
OMIM611066   
Gene and transcription
Genbank (Entrez)AB023148 AK001661 AK001854 AK124678 AM393067
RefSeq transcript (Entrez)NM_001289003 NM_015020
RefSeq genomic (Entrez)AC_000148 NC_000016 NC_018927 NT_010498 NW_001838325 NW_004929402
Consensus coding sequences : CCDS (NCBI)PHLPP2
Cluster EST : UnigeneHs.709458 [ NCBI ]
CGAP (NCI)Hs.709458
Alternative Splicing : Fast-db (Paris)GSHG0011963
Alternative Splicing GalleryENSG00000040199
Gene ExpressionPHLPP2 [ NCBI-GEO ]     PHLPP2 [ SEEK ]   PHLPP2 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ6ZVD8 (Uniprot)
NextProtQ6ZVD8  [Medical]
With graphics : InterProQ6ZVD8
Splice isoforms : SwissVarQ6ZVD8 (Swissvar)
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 ]   
Domaine pattern : Prosite (Expaxy)LRR (PS51450)   
Domains : Interpro (EBI)Leu-rich_rpt [organisation]   Leu-rich_rpt_typical-subtyp [organisation]   PP2C-like_dom [organisation]  
Related proteins : CluSTrQ6ZVD8
Domain families : Pfam (Sanger)LRR_1 (PF00560)    LRR_8 (PF13855)    PP2C (PF00481)   
Domain families : Pfam (NCBI)pfam00560    pfam13855    pfam00481   
Domain families : Smart (EMBL)LRR_TYP (SM00369)  PP2Cc (SM00332)  
DMDM Disease mutations23035
Blocks (Seattle)Q6ZVD8
Human Protein AtlasENSG00000040199 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ6ZVD8
HPRD11118
IPIIPI00176709   IPI00477369   IPI00718931   IPI00828193   IPI00641240   IPI01009123   IPI01012658   
Protein Interaction databases
DIP (DOE-UCLA)Q6ZVD8
IntAct (EBI)Q6ZVD8
FunCoupENSG00000040199
BioGRIDPHLPP2
InParanoidQ6ZVD8
Interologous Interaction database Q6ZVD8
IntegromeDBPHLPP2
STRING (EMBL)PHLPP2
Ontologies - Pathways
Ontology : AmiGOphotoreceptor inner segment  protein serine/threonine phosphatase activity  nucleus  cytoplasm  cytosol  protein dephosphorylation  epidermal growth factor receptor signaling pathway  fibroblast growth factor receptor signaling pathway  Fc-epsilon receptor signaling pathway  photoreceptor outer segment membrane  innate immune response  metal ion binding  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  
Ontology : EGO-EBIphotoreceptor inner segment  protein serine/threonine phosphatase activity  nucleus  cytoplasm  cytosol  protein dephosphorylation  epidermal growth factor receptor signaling pathway  fibroblast growth factor receptor signaling pathway  Fc-epsilon receptor signaling pathway  photoreceptor outer segment membrane  innate immune response  metal ion binding  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  
Pathways : KEGGPI3K-Akt signaling pathway   
Protein Interaction DatabasePHLPP2
Wikipedia pathwaysPHLPP2
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)PHLPP2
snp3D : Map Gene to Disease23035
SNP (GeneSNP Utah)PHLPP2
SNP : HGBasePHLPP2
Genetic variants : HAPMAPPHLPP2
Exome VariantPHLPP2
1000_GenomesPHLPP2 
ICGC programENSG00000040199 
Somatic Mutations in Cancer : COSMICPHLPP2 
CONAN: Copy Number AnalysisPHLPP2 
Mutations and Diseases : HGMDPHLPP2
Genomic VariantsPHLPP2  PHLPP2 [DGVbeta]
dbVarPHLPP2
ClinVarPHLPP2
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM611066   
MedgenPHLPP2
GENETestsPHLPP2
Disease Genetic AssociationPHLPP2
Huge Navigator PHLPP2 [HugePedia]  PHLPP2 [HugeCancerGEM]
General knowledge
Homologs : HomoloGenePHLPP2
Homology/Alignments : Family Browser (UCSC)PHLPP2
Phylogenetic Trees/Animal Genes : TreeFamPHLPP2
Chemical/Protein Interactions : CTD23035
Chemical/Pharm GKB GenePA165450496
Clinical trialPHLPP2
Cancer Resource (Charite)ENSG00000040199
Other databases
Probes
Litterature
PubMed22 Pubmed reference(s) in Entrez
CoreMinePHLPP2
iHOPPHLPP2
OncoSearchPHLPP2

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
 
PHLPPing it off: phosphatases get in the Akt.
Mendoza MC, Blenis J.
Mol Cell. 2007 Mar 23;25(6):798-800. (REVIEW)
PMID 17386258
 
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
 
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
 
Common polymorphism in the phosphatase PHLPP2 results in reduced regulation of Akt and protein kinase C.
Brognard J, Niederst M, Reyes G, Warfel N, Newton AC.
J Biol Chem. 2009 May 29;284(22):15215-23.
PMID 19324870
 
Activation of PH-domain leucine-rich protein phosphatase 2 (PHLPP2) by agonist stimulation in cardiac myocytes expressing adenylyl cyclase type 6.
Gao MH, Miyanohara A, Feramisco JR, Tang T.
Biochem Biophys Res Commun. 2009 Jun 26;384(2):193-8.
PMID 19450723
 
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
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written06-2009Audrey K O'Neill, Alexandra C Newton
Department of Pharmacology, University of California San Diego, 9500 Gilman Dr., Mail Code 0721, La Jolla, CA 92093, USA

Citation

This paper should be referenced as such :
O'Neill, AK ; Newton, AC
PHLPP2 (PH domain leucine-rich repeat protein phosphatase 2)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(5):-.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/PHLPP2ID44546ch16q22.html

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indexed on : Sat Jul 26 15:08:34 CEST 2014

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