Atlas of Genetics and Cytogenetics in Oncology and Haematology

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

Written2009-06Audrey 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

(Note : for Links provided by Atlas : click)


HGNC Alias symbKIAA0931
HGNC Alias name"protein phosphatase, Mg2+/Mn2+ dependent 3B"
HGNC Previous namePHLPPL
HGNC Previous namePH domain and leucine rich repeat protein phosphatase-like
LocusID (NCBI) 23035
Atlas_Id 44546
Location 16q22.2  [Link to chromosome band 16q22]
Location_base_pair Starts at 71644926 and ends at 71724701 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping PHLPP2.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)
CHD3 (17p13.1) / PHLPP2 (16q22.2)PHLPP2 (16q22.2) / KIF22 (16p11.2)PHLPP2 (16q22.2) / PHLPP2 (16q22.2)
SORBS2 (4q35.1) / PHLPP2 (16q22.2)SP100 (2q37.1) / PHLPP2 (16q22.2)


  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.


  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.


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.


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
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
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
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
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


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):467-469.
Free journal version : [ pdf ]   [ DOI ]

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(16;16)(p11;q22) PHLPP2/KIF22

External links

HGNC (Hugo)PHLPP2   29149
Entrez_Gene (NCBI)PHLPP2    PH domain and leucine rich repeat protein phosphatase 2
GeneCards (Weizmann)PHLPP2
Ensembl hg19 (Hinxton)ENSG00000040199 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000040199 [Gene_View]  ENSG00000040199 [Sequence]  chr16:71644926-71724701 [Contig_View]  PHLPP2 [Vega]
ICGC DataPortalENSG00000040199
Genatlas (Paris)PHLPP2
SOURCE (Princeton)PHLPP2
Genetics Home Reference (NIH)PHLPP2
Genomic and cartography
GoldenPath hg38 (UCSC)PHLPP2  -     chr16:71644926-71724701 -  16q22.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PHLPP2  -     16q22.2   [Description]    (hg19-Feb_2009)
GoldenPathPHLPP2 - 16q22.2 [CytoView hg19]  PHLPP2 - 16q22.2 [CytoView hg38]
genome Data Viewer NCBIPHLPP2 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AB023148 AK001661 AK001854 AK124678 BC035267
RefSeq transcript (Entrez)NM_001289003 NM_015020
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)PHLPP2
Alternative Splicing GalleryENSG00000040199
Gene ExpressionPHLPP2 [ NCBI-GEO ]   PHLPP2 [ EBI - ARRAY_EXPRESS ]   PHLPP2 [ SEEK ]   PHLPP2 [ MEM ]
Gene Expression Viewer (FireBrowse)PHLPP2 [ Firebrowse - Broad ]
GenevisibleExpression of PHLPP2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)23035
GTEX Portal (Tissue expression)PHLPP2
Human Protein AtlasENSG00000040199-PHLPP2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ6ZVD8   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ6ZVD8  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ6ZVD8
Splice isoforms : SwissVarQ6ZVD8
Domaine pattern : Prosite (Expaxy)LRR (PS51450)    PPM_2 (PS51746)   
Domains : Interpro (EBI)Leu-rich_rpt    Leu-rich_rpt_typical-subtyp    LRR_dom_sf    PPM-type_dom_sf    PPM-type_phosphatase_dom   
Domain families : Pfam (Sanger)LRR_8 (PF13855)    PP2C (PF00481)   
Domain families : Pfam (NCBI)pfam13855    pfam00481   
Domain families : Smart (EMBL)LRR_TYP (SM00369)  PP2Cc (SM00332)  
Conserved Domain (NCBI)PHLPP2
Blocks (Seattle)PHLPP2
Human Protein Atlas [tissue]ENSG00000040199-PHLPP2 [tissue]
Peptide AtlasQ6ZVD8
IPIIPI00176709   IPI00477369   IPI00718931   IPI00828193   IPI00641240   IPI01009123   IPI01012658   
Protein Interaction databases
IntAct (EBI)Q6ZVD8
Ontologies - Pathways
Ontology : AmiGOphotoreceptor inner segment  protein serine/threonine phosphatase activity  protein binding  nucleus  cytoplasm  cytoplasm  cytosol  protein dephosphorylation  signal transduction  inorganic anion transport  hippocampus development  photoreceptor outer segment membrane  intracellular membrane-bounded organelle  metal ion binding  negative regulation of protein kinase B signaling  
Ontology : EGO-EBIphotoreceptor inner segment  protein serine/threonine phosphatase activity  protein binding  nucleus  cytoplasm  cytoplasm  cytosol  protein dephosphorylation  signal transduction  inorganic anion transport  hippocampus development  photoreceptor outer segment membrane  intracellular membrane-bounded organelle  metal ion binding  negative regulation of protein kinase B signaling  
Pathways : KEGGPI3K-Akt signaling pathway   
REACTOMEQ6ZVD8 [protein]
REACTOME PathwaysR-HSA-199418 [pathway]   
NDEx NetworkPHLPP2
Atlas of Cancer Signalling NetworkPHLPP2
Wikipedia pathwaysPHLPP2
Orthology - Evolution
GeneTree (enSembl)ENSG00000040199
Phylogenetic Trees/Animal Genes : TreeFamPHLPP2
Homologs : HomoloGenePHLPP2
Homology/Alignments : Family Browser (UCSC)PHLPP2
Gene fusions - Rearrangements
Fusion : MitelmanPHLPP2/KIF22 [16q22.2/16p11.2]  
Fusion PortalPHLPP2 16q22.2 KIF22 16p11.2 LUAD
Fusion : FusionGDB3.1.3.16   
Fusion : Fusion_HubCHD3--PHLPP2    EEF2--PHLPP2    LIMCH1--PHLPP2    PHLPP2--CHMP2B    PHLPP2--KIF22    PHLPP2--PHLPP2    PHLPP2--ZBTB38    PHLPP2--ZNF821    SORBS2--PHLPP2    SP100--PHLPP2   
Fusion : QuiverPHLPP2
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPHLPP2 [hg38]
Exome Variant ServerPHLPP2
GNOMAD BrowserENSG00000040199
Varsome BrowserPHLPP2
Genomic Variants (DGV)PHLPP2 [DGVbeta]
DECIPHERPHLPP2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPHLPP2 
ICGC Data PortalPHLPP2 
TCGA Data PortalPHLPP2 
Broad Tumor PortalPHLPP2
OASIS PortalPHLPP2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPHLPP2  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DPHLPP2
Mutations and Diseases : HGMDPHLPP2
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 PHLPP2
DgiDB (Drug Gene Interaction Database)PHLPP2
DoCM (Curated mutations)PHLPP2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PHLPP2 (select a term)
NCG6 (London) select PHLPP2
Cancer3DPHLPP2(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry PHLPP2
NextProtQ6ZVD8 [Medical]
Target ValidationPHLPP2
Huge Navigator PHLPP2 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTD
Pharm GKB GenePA165450496
Clinical trialPHLPP2
canSAR (ICR)PHLPP2 (select the gene name)
DataMed IndexPHLPP2
PubMed62 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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