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PEA15 (phosphoprotein enriched in astrocytes 15)

Written2012-05Chandra Bartholomeusz, Jangsoon Lee, Naoto T Ueno
Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

(Note : for Links provided by Atlas : click)


HGNC (Hugo) PEA15
HGNC Alias symbHMAT1
HGNC Alias namePhosphoprotein enriched in astrocytes, 15kD
 homolog of mouse MAT-1 oncogene
 Phosphoprotein enriched in diabetes
HGNC Previous namephosphoprotein enriched in astrocytes 15
 proliferation and apoptosis adaptor 15
LocusID (NCBI) 8682
Atlas_Id 46286
Location 1q23.2  [Link to chromosome band 1q23]
Location_base_pair Starts at 160205384 and ends at 160215372 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping PEA15.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)
GAPDH (12p13.31)::PEA15 (1q23.2)PEA15 (1q23.2)::CDH2 (18q12.1)PEA15 (1q23.2)::INS-IGF2 (11p15.5)
PEA15 (1q23.2)::PEA15 (1q23.2)SF3A1 (22q12.2)::PEA15 (1q23.2)


  Structure of the human PEA15 gene. Red box: PEA15 coding region; blue box: PEA15 non-coding region; white box: 3' end of H326 region; SNP position: indicated by vertical arrows; Alu element (AA491823) 5' of PEA15: represented by brackets (Wolford et al., 2000, license permission no.: 2907741403264).
Description According to Entrez Gene, PEA15 maps to NC_000001.10 and spans a region of 10042 bases. PEA15 consists of four exons. Exon 1 and the beginning of exon 2 contain untranslated sequences. The end of exon 2, exon 3, and the beginning of exon 4 contain the coding sequence.
Transcription Two transcripts, with lengths of 2,5 and 1,7 kb, have been identified. They are identical except for the length of their 3' UTRs.
Pseudogene No pseudogene of PEA15 known.


  DED: death effector domain, amino acid region 3-81, Pfam: PF01335 (Sanger); NES: leucine-rich nuclear export sequence, amino acid region 7-17; MT: microtubule-binding region, amino acid region 98-107, and 122-129; PLD-1 binding region: phospholipase D1 binding site, amino acid region 1-24; ERK binding site: amino acid position 74, 121, 123, and 129; RSK2 binding site: amino acid position 123; Serine 104: phosphorylation site by PKC; Serine 116: phosphorylation site by AKT or CaKMII.
Description PEA-15 is a 130-amino-acid protein with a predicted molecular mass of 15054 daltons and a calculated isoelectric point of 5.12.
Expression Ovary, breast, brain, placenta, liver, eye, lung, heart, endothelial cells, pancreas, testis, uterus, adrenal gland, prostate gland, kidney, spleen, and astrocytes.
Localisation Cytoplasm. PEA-15 has a leucine-rich nuclear export sequence (NES), which is required for predominantly localizing in the cytoplasm (Formstecher et al., 2001).
Function PEA-15 is a ubiquitously expressed protein that exists in non-phosphorylated, mono-phosphorylated, and double-phosphorylated forms (Danziger et al., 1995). PEA-15 does not have an enzymatic domain but serves as a binding molecule in protein complexes. PEA-15 is an endogenous substrate that depends on two distinct serine sites: Ser104, which is phosphorylated by protein kinase C (PKC) (Kubes et al., 1998), and Ser116, which is phosphorylated by Ca2+/calmodulin kinase II (CaMKII) (Kubes et al., 1998) or by AKT (Trencia et al., 2003). At its NH2 terminus, PEA-15 has a PLD-interacting region, which enhances PLD 1 stability and activity (Zhang et al., 2000), and a death effector domain (DED), which enables interaction with DED-containing signaling proteins, including Fas-associated protein with death domain (FADD) and FADD-like IL-1β-converting enzyme (Peter et al., 1999). At its COOH terminus, PEA-15 has a microtubule-binding region, which regulates the stability of tubulins (Danziger et al., 1995).
ERK inhibition. PEA-15 can bind to ERK and sequester it in the cytoplasm. The resulting inhibition of ERK's translocalization into the nucleus blocks ERK-dependent transcriptional activity and cell proliferation (Formstecher et al., 2001).
Apoptosis and anti-apoptosis. PEA-15 interacts with different DED-containing proteins such as FADD and FLICE and inhibits Fas/TNFR1-induced apoptosis by preventing formation of the death-inducing signaling complex (DISC) (Condorelli et al., 1999; Song et al., 2006). On the other hand, under different cellular stresses, PEA-15 acts as a substrate of Omi/HtrA2, which is a proapoptotic mitochondrial serine protease; it results in reducing anti-apoptotic action of Omi/HtrA2 and triggering apoptotic programs (Trencia et al., 2004).
Metabolism. In skeletal muscle and adipose cells, PEA-15 binds to PLD1 and enhances PKC-α activity, thereby inducing resistance to insulin action in glucose uptake (Condorelli et al., 1998).
Invasion. A high expression level of PEA-15 is correlated with low invasive behavior of breast cancer (Glading et al., 2007). PEA-15's prevention of ERK's nuclear localization results in reduced invasion capability in breast cancer.
Tumorigenicity. In human breast cancers, low levels of PEA-15 expression correlated with high nuclear grade and with negative hormone receptor status. Overexpression of PEA-15 in breast cancer cells resulted in growth inhibition, reduction in DNA synthesis, and onset of caspase-8-dependent apoptosis (Bartholomeusz et al., 2010). In transgenic mice with overexpression of PEA-15, its expression level had a significant impact on skin tumor development upon chemically induced skin carcinogenesis (Formisano et al., 2005). In in vitro studies, PEA-15 enhanced Ras-MAPK/ERK signaling in the presence of constitutively active H-Ras and drove transformation of kidney epithelial cells (Sulzmaier et al., 2012; Ramos et al., 2000).
Homology The mouse and human sequences are conserved. In both species, the 3' UTR of the 2,5-kb PEA15 cDNA contains the proto-oncogene MAT1 (Tsukamoto et al., 2000).


Note No known mutations have been reported.

Implicated in

Entity Breast cancer
Note See above "Invasion" and "Tumorigenicity" sections.
Entity Ovarian cancer
Prognosis In ovarian cancer, women with high PEA-15-expressing tumors survive longer than those with low PEA-15-expressing tumors, indicating that PEA-15 is a good prognostic marker (Bartholomeusz et al., 2008).
Entity Astrocytic tumors
Prognosis In astrocytic tumors, decreased PEA-15 expression level was correlated with poor overall survival in patients with high-grade astrocytoma (Watanabe et al., 2010).
Entity Neuroblastoma
Prognosis High levels of PEA-15 expression correlated with increased survival of patients with neuroblastoma (Gawecka et al., 2012).
Entity Skin tumors
Oncogenesis PEA-15 increases the susceptibility to chemically induced skin cancer in transgenic mice (Formisano et al., 2005).


PEA-15 inhibits tumorigenesis in an MDA-MB-468 triple-negative breast cancer xenograft model through increased cytoplasmic localization of activated extracellular signal-regulated kinase.
Bartholomeusz C, Gonzalez-Angulo AM, Kazansky A, Krishnamurthy S, Liu P, Yuan LX, Yamasaki F, Liu S, Hayashi N, Zhang D, Esteva FJ, Hortobagyi GN, Ueno NT.
Clin Cancer Res. 2010 Mar 15;16(6):1802-11. Epub 2010 Mar 9.
PMID 20215547
PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis.
Condorelli G, Vigliotta G, Cafieri A, Trencia A, Andalo P, Oriente F, Miele C, Caruso M, Formisano P, Beguinot F.
Oncogene. 1999 Aug 5;18(31):4409-15.
PMID 10442631
Cellular expression, developmental regulation, and phylogenic conservation of PEA-15, the astrocytic major phosphoprotein and protein kinase C substrate.
Danziger N, Yokoyama M, Jay T, Cordier J, Glowinski J, Chneiweiss H.
J Neurochem. 1995 Mar;64(3):1016-25.
PMID 7861130
The major astrocytic phosphoprotein PEA-15 is encoded by two mRNAs conserved on their full length in mouse and human.
Estelles A, Yokoyama M, Nothias F, Vincent JD, Glowinski J, Vernier P, Chneiweiss H.
J Biol Chem. 1996 Jun 21;271(25):14800-6.
PMID 8662970
Raised expression of the antiapoptotic protein ped/pea-15 increases susceptibility to chemically induced skin tumor development.
Formisano P, Perruolo G, Libertini S, Santopietro S, Troncone G, Raciti GA, Oriente F, Portella G, Miele C, Beguinot F.
Oncogene. 2005 Oct 27;24(47):7012-21.
PMID 16044159
PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase.
Formstecher E, Ramos JW, Fauquet M, Calderwood DA, Hsieh JC, Canton B, Nguyen XT, Barnier JV, Camonis J, Ginsberg MH, Chneiweiss H.
Dev Cell. 2001 Aug;1(2):239-50.
PMID 11702783
PEA15 impairs cell migration and correlates with clinical features predicting good prognosis in neuroblastoma.
Gawecka JE, Geerts D, Koster J, Caliva MJ, Sulzmaier FJ, Opoku-Ansah J, Wada RK, Bachmann AS, Ramos JW.
Int J Cancer. 2012 Oct 1;131(7):1556-68. doi: 10.1002/ijc.27415. Epub 2012 Jan 31.
PMID 22213050
PEA-15 inhibits tumor cell invasion by binding to extracellular signal-regulated kinase 1/2.
Glading A, Koziol JA, Krueger J, Ginsberg MH.
Cancer Res. 2007 Feb 15;67(4):1536-44.
PMID 17308092
Endothelin induces a calcium-dependent phosphorylation of PEA-15 in intact astrocytes: identification of Ser104 and Ser116 phosphorylated, respectively, by protein kinase C and calcium/calmodulin kinase II in vitro.
Kubes M, Cordier J, Glowinski J, Girault JA, Chneiweiss H.
J Neurochem. 1998 Sep;71(3):1307-14.
PMID 9721757
The death receptors.
Peter ME, Scaffidi C, Medema JP, Kischkel F, Krammer PH.
Results Probl Cell Differ. 1999;23:25-63. (REVIEW)
PMID 9950028
Death effector domain protein PEA-15 potentiates Ras activation of extracellular signal receptor-activated kinase by an adhesion-independent mechanism.
Ramos JW, Hughes PE, Renshaw MW, Schwartz MA, Formstecher E, Chneiweiss H, Ginsberg MH.
Mol Biol Cell. 2000 Sep;11(9):2863-72.
PMID 10982386
Human astrocytes are resistant to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis.
Song JH, Bellail A, Tse MC, Yong VW, Hao C.
J Neurosci. 2006 Mar 22;26(12):3299-308.
PMID 16554480
PED mediates AKT-dependent chemoresistance in human breast cancer cells.
Stassi G, Garofalo M, Zerilli M, Ricci-Vitiani L, Zanca C, Todaro M, Aragona F, Limite G, Petrella G, Condorelli G.
Cancer Res. 2005 Aug 1;65(15):6668-75.
PMID 16061647
PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase D.
Sulzmaier FJ, Valmiki MK, Nelson DA, Caliva MJ, Geerts D, Matter ML, White EP, Ramos JW.
Oncogene. 2012 Jul 26;31(30):3547-60. doi: 10.1038/onc.2011.514. Epub 2011 Nov 21.
PMID 22105357
Omi/HtrA2 promotes cell death by binding and degrading the anti-apoptotic protein ped/pea-15.
Trencia A, Fiory F, Maitan MA, Vito P, Barbagallo AP, Perfetti A, Miele C, Ungaro P, Oriente F, Cilenti L, Zervos AS, Formisano P, Beguinot F.
J Biol Chem. 2004 Nov 5;279(45):46566-72. Epub 2004 Aug 24.
PMID 15328349
Protein kinase B/Akt binds and phosphorylates PED/PEA-15, stabilizing its antiapoptotic action.
Trencia A, Perfetti A, Cassese A, Vigliotta G, Miele C, Oriente F, Santopietro S, Giacco F, Condorelli G, Formisano P, Beguinot F.
Mol Cell Biol. 2003 Jul;23(13):4511-21.
PMID 12808093
Expression of MAT1/PEA-15 mRNA isoforms during physiological and neoplastic changes in the mouse mammary gland.
Tsukamoto T, Yoo J, Hwang SI, Guzman RC, Hirokawa Y, Chou YC, Olatunde S, Huang T, Bera TK, Yang J, Nandi S.
Cancer Lett. 2000 Feb 28;149(1-2):105-13.
PMID 10737714
Expression of phosphoprotein enriched in astrocytes 15 kDa (PEA-15) in astrocytic tumors: a novel approach of correlating malignancy grade and prognosis.
Watanabe Y, Yamasaki F, Kajiwara Y, Saito T, Nishimoto T, Bartholomeusz C, Ueno NT, Sugiyama K, Kurisu K.
J Neurooncol. 2010 Dec;100(3):449-57. Epub 2010 May 9.
PMID 20455002
Molecular characterization of the human PEA15 gene on 1q21-q22 and association with type 2 diabetes mellitus in Pima Indians.
Wolford JK, Bogardus C, Ossowski V, Prochazka M.
Gene. 2000 Jan 4;241(1):143-8.
PMID 10607908
Regulation of expression of phospholipase D1 and D2 by PEA-15, a novel protein that interacts with them.
Zhang Y, Redina O, Altshuller YM, Yamazaki M, Ramos J, Chneiweiss H, Kanaho Y, Frohman MA.
J Biol Chem. 2000 Nov 10;275(45):35224-32.
PMID 10926929


This paper should be referenced as such :
Bartholomeusz, C ; Lee, J ; Ueno, NT
PEA15 (phosphoprotein enriched in astrocytes 15)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(10):732-735.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)PEA15   8822
Entrez_Gene (NCBI)PEA15    proliferation and apoptosis adaptor protein 15
GeneCards (Weizmann)PEA15
Ensembl hg19 (Hinxton)ENSG00000162734 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000162734 [Gene_View]  ENSG00000162734 [Sequence]  chr1:160205384-160215372 [Contig_View]  PEA15 [Vega]
ICGC DataPortalENSG00000162734
TCGA cBioPortalPEA15
AceView (NCBI)PEA15
Genatlas (Paris)PEA15
SOURCE (Princeton)PEA15
Genetics Home Reference (NIH)PEA15
Genomic and cartography
GoldenPath hg38 (UCSC)PEA15  -     chr1:160205384-160215372 +  1q23.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PEA15  -     1q23.2   [Description]    (hg19-Feb_2009)
GoldenPathPEA15 - 1q23.2 [CytoView hg19]  PEA15 - 1q23.2 [CytoView hg38]
Genome Data Viewer NCBIPEA15 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AA837443 AI948916 AK095879 AK311762 BC002426
RefSeq transcript (Entrez)NM_001297576 NM_001297577 NM_001297578 NM_003768
Consensus coding sequences : CCDS (NCBI)PEA15
Gene ExpressionPEA15 [ NCBI-GEO ]   PEA15 [ EBI - ARRAY_EXPRESS ]   PEA15 [ SEEK ]   PEA15 [ MEM ]
Gene Expression Viewer (FireBrowse)PEA15 [ Firebrowse - Broad ]
GenevisibleExpression of PEA15 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8682
GTEX Portal (Tissue expression)PEA15
Human Protein AtlasENSG00000162734-PEA15 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ15121   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ15121  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ15121
Domaine pattern : Prosite (Expaxy)DED (PS50168)   
Domains : Interpro (EBI)DEATH-like_dom_sf    DED_dom    PEA15_DED   
Domain families : Pfam (Sanger)DED (PF01335)   
Domain families : Pfam (NCBI)pfam01335   
Domain families : Smart (EMBL)DED (SM00031)  
Conserved Domain (NCBI)PEA15
PDB (RSDB)4IZ5    4IZA    6P6B    6P6C   
PDB Europe4IZ5    4IZA    6P6B    6P6C   
PDB (PDBSum)4IZ5    4IZA    6P6B    6P6C   
PDB (IMB)4IZ5    4IZA    6P6B    6P6C   
Structural Biology KnowledgeBase4IZ5    4IZA    6P6B    6P6C   
SCOP (Structural Classification of Proteins)4IZ5    4IZA    6P6B    6P6C   
CATH (Classification of proteins structures)4IZ5    4IZA    6P6B    6P6C   
AlphaFold pdb e-kbQ15121   
Human Protein Atlas [tissue]ENSG00000162734-PEA15 [tissue]
Protein Interaction databases
IntAct (EBI)Q15121
Ontologies - Pathways
Ontology : AmiGOMAPK cascade  activation of MAPK activity  protein binding  nucleoplasm  cytosol  cytosol  microtubule associated complex  apoptotic process  carbohydrate transport  response to morphine  negative regulation of glucose import  negative regulation of extrinsic apoptotic signaling pathway via death domain receptors  negative regulation of extrinsic apoptotic signaling pathway via death domain receptors  positive regulation of extrinsic apoptotic signaling pathway via death domain receptors  
Ontology : EGO-EBIMAPK cascade  activation of MAPK activity  protein binding  nucleoplasm  cytosol  cytosol  microtubule associated complex  apoptotic process  carbohydrate transport  response to morphine  negative regulation of glucose import  negative regulation of extrinsic apoptotic signaling pathway via death domain receptors  negative regulation of extrinsic apoptotic signaling pathway via death domain receptors  positive regulation of extrinsic apoptotic signaling pathway via death domain receptors  
REACTOMEQ15121 [protein]
REACTOME PathwaysR-HSA-5673001 [pathway]   
NDEx NetworkPEA15
Atlas of Cancer Signalling NetworkPEA15
Wikipedia pathwaysPEA15
Orthology - Evolution
GeneTree (enSembl)ENSG00000162734
Phylogenetic Trees/Animal Genes : TreeFamPEA15
Homologs : HomoloGenePEA15
Homology/Alignments : Family Browser (UCSC)PEA15
Gene fusions - Rearrangements
Fusion : QuiverPEA15
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPEA15 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PEA15
Exome Variant ServerPEA15
GNOMAD BrowserENSG00000162734
Varsome BrowserPEA15
ACMGPEA15 variants
Genomic Variants (DGV)PEA15 [DGVbeta]
DECIPHERPEA15 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPEA15 
ICGC Data PortalPEA15 
TCGA Data PortalPEA15 
Broad Tumor PortalPEA15
OASIS PortalPEA15 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPEA15  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DPEA15
Mutations and Diseases : HGMDPEA15
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)PEA15
DoCM (Curated mutations)PEA15
CIViC (Clinical Interpretations of Variants in Cancer)PEA15
NCG (London)PEA15
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry PEA15
NextProtQ15121 [Medical]
Target ValidationPEA15
Huge Navigator PEA15 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDPEA15
Pharm GKB GenePA33166
Clinical trialPEA15
DataMed IndexPEA15
PubMed97 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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indexed on : Fri Oct 8 21:24:53 CEST 2021

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