PHLA2_HUMAN
ID PHLA2_HUMAN Reviewed; 152 AA.
AC Q53GA4; O00496;
DT 20-DEC-2005, integrated into UniProtKB/Swiss-Prot.
DT 20-DEC-2005, sequence version 2.
DT 03-AUG-2022, entry version 131.
DE RecName: Full=Pleckstrin homology-like domain family A member 2;
DE AltName: Full=Beckwith-Wiedemann syndrome chromosomal region 1 candidate gene C protein;
DE AltName: Full=Imprinted in placenta and liver protein;
DE AltName: Full=Tumor-suppressing STF cDNA 3 protein;
DE AltName: Full=Tumor-suppressing subchromosomal transferable fragment candidate gene 3 protein;
DE AltName: Full=p17-Beckwith-Wiedemann region 1 C;
DE Short=p17-BWR1C;
GN Name=PHLDA2; Synonyms=BWR1C, HLDA2, IPL, TSSC3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9403053; DOI=10.1006/geno.1997.4981;
RA Hu R.-J., Lee M.P., Connors T.D., Johnson L.A., Burn T.C., Su K.,
RA Landes G.M., Feinberg A.P.;
RT "A 2.5-Mb transcript map of a tumor-suppressing subchromosomal transferable
RT fragment from 11p15.5, and isolation and sequence analysis of three novel
RT genes.";
RL Genomics 46:9-17(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RX PubMed=9328465; DOI=10.1093/hmg/6.12.2021;
RA Qian N., Frank D., O'Keefe D., Dao D., Zhao L., Yuan L., Wang Q.,
RA Keating M., Walsh C., Tycko B.;
RT "The IPL gene on chromosome 11p15.5 is imprinted in humans and mice and is
RT similar to TDAG51, implicated in Fas expression and apoptosis.";
RL Hum. Mol. Genet. 6:2021-2029(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9520460; DOI=10.1073/pnas.95.7.3873;
RA Schwienbacher C., Sabbioni S., Campi M., Veronese A., Bernardi G.,
RA Menegatti A., Hatada I., Mukai T., Ohashi H., Barbanti-Brodano G.,
RA Croce C.M., Negrini M.;
RT "Transcriptional map of 170-kb region at chromosome 11p15.5: identification
RT and mutational analysis of the BWR1A gene reveals the presence of mutations
RT in tumor samples.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:3873-3878(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Umbilical vein;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP TISSUE SPECIFICITY.
RX PubMed=10594239; DOI=10.1007/s003359901182;
RA Frank D., Mendelsohn C.L., Ciccone E., Svensson K., Ohlsson R., Tycko B.;
RT "A novel pleckstrin homology-related gene family defined by Ipl/Tssc3,
RT TDAG51, and Tih1: tissue-specific expression, chromosomal location, and
RT parental imprinting.";
RL Mamm. Genome 10:1150-1159(1999).
RN [8]
RP TISSUE SPECIFICITY.
RX PubMed=10749982; DOI=10.1093/hmg/9.5.757;
RA Mueller S., van den Boom D., Zirkel D., Koester H., Berthold F., Schwab M.,
RA Westphal M., Zumkeller W.;
RT "Retention of imprinting of the human apoptosis-related gene TSSC3 in human
RT brain tumors.";
RL Hum. Mol. Genet. 9:757-763(2000).
RN [9]
RP TISSUE SPECIFICITY.
RX PubMed=13129680; DOI=10.1016/s0143-4004(03)00130-9;
RA Saxena A., Frank D., Panichkul P., Van den Veyver I.B., Tycko B.,
RA Thaker H.;
RT "The product of the imprinted gene IPL marks human villous cytotrophoblast
RT and is lost in complete hydatidiform mole.";
RL Placenta 24:835-842(2003).
RN [10]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=15457853;
RA Thaker H.M., Berlin A., Tycko B., Goldstein D.P., Berkowitz R.S.,
RA Castrillon D.H., Genest D.R.;
RT "Immunohistochemistry for the imprinted gene product IPL/PHLDA2 for
RT facilitating the differential diagnosis of complete hydatidiform mole.";
RL J. Reprod. Med. 49:630-636(2004).
RN [11]
RP INDUCTION, AND IMPRINTING.
RX PubMed=15314611; DOI=10.1038/modpathol.3800175;
RA Fisher R.A., Nucci M.R., Thaker H.M., Weremowicz S., Genest D.R.,
RA Castrillon D.H.;
RT "Complete hydatidiform mole retaining a chromosome 11 of maternal origin:
RT molecular genetic analysis of a case.";
RL Mod. Pathol. 17:1155-1160(2004).
RN [12]
RP IMPRINTING.
RX PubMed=17303335; DOI=10.1016/j.bbagen.2007.01.004;
RA Tang K.-F., Wang Y., Wang P., Chen M., Chen Y., Hu H.-D., Hu P., Wang B.,
RA Yang W., Ren H.;
RT "Upregulation of PHLDA2 in Dicer knockdown HEK293 cells.";
RL Biochim. Biophys. Acta 1770:820-825(2007).
RN [13]
RP INDUCTION.
RX PubMed=16584773; DOI=10.1016/j.placenta.2006.01.025;
RA Kim H.-S., Roh C.-R., Chen B., Tycko B., Nelson D.M., Sadovsky Y.;
RT "Hypoxia regulates the expression of PHLDA2 in primary term human
RT trophoblasts.";
RL Placenta 28:77-84(2007).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3; SER-141 AND SER-144, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-42; SER-144 AND THR-151, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [16]
RP LACK OF INDUCTION BY TP53.
RX PubMed=19203586; DOI=10.1016/j.cell.2008.12.002;
RA Kawase T., Ohki R., Shibata T., Tsutsumi S., Kamimura N., Inazawa J.,
RA Ohta T., Ichikawa H., Aburatani H., Tashiro F., Taya Y.;
RT "PH domain-only protein PHLDA3 is a p53-regulated repressor of Akt.";
RL Cell 136:535-550(2009).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-42, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3 AND SER-42, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
CC -!- FUNCTION: Plays a role in regulating placenta growth. May act via its
CC PH domain that competes with other PH domain-containing proteins,
CC thereby preventing their binding to membrane lipids (By similarity).
CC {ECO:0000250}.
CC -!- INTERACTION:
CC Q53GA4; A0A0C3SFZ9: FCHO1; NbExp=3; IntAct=EBI-4402464, EBI-11977403;
CC Q53GA4; Q96DC9: OTUB2; NbExp=3; IntAct=EBI-4402464, EBI-746259;
CC Q53GA4; Q16385-2: SSX2B; NbExp=3; IntAct=EBI-4402464, EBI-17564583;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Membrane {ECO:0000250};
CC Peripheral membrane protein {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Expressed in placenta and adult prostate gland. In
CC placenta, it is present in all cells of the villous cytotrophoblast.
CC The protein is absent in cells from hydatidiform moles. Hydatidiform
CC mole is a gestation characterized by abnormal development of both fetus
CC and trophoblast. The majority of hydatidiform moles are associated with
CC an excess of paternal to maternal genomes and are likely to result from
CC the abnormal expression of imprinted genes (at protein level).
CC Expressed at low levels in adult liver and lung, and fetal liver.
CC Expressed in adult brain and neuroblastoma, medullablastoma and
CC glioblastoma cell lines. {ECO:0000269|PubMed:10594239,
CC ECO:0000269|PubMed:10749982, ECO:0000269|PubMed:13129680,
CC ECO:0000269|PubMed:15457853, ECO:0000269|PubMed:9328465}.
CC -!- INDUCTION: Maternal PHLDA2 allele is activated, while paternal Phlda2
CC is repressed due to genomic imprinting. Down-regulated by hypoxia.
CC Although highly similar to PHLDA3 protein, it is not regulated by
CC p53/TP53. {ECO:0000269|PubMed:15314611, ECO:0000269|PubMed:16584773}.
CC -!- DOMAIN: The PH domain binds phosphoinositides with a broad specificity.
CC It may compete with the PH domain of some other proteins, thereby
CC interfering with their binding to phosphatidylinositol 4,5-bisphosphate
CC (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) (By
CC similarity). {ECO:0000250}.
CC -!- MISCELLANEOUS: The PHLDA2 locus is imprinted. Loss of imprinting
CC results in overexpression. Imprinting is dependent on RNAi machinery.
CC -!- SIMILARITY: Belongs to the PHLDA2 family. {ECO:0000305}.
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DR EMBL; AF019953; AAC51912.1; -; mRNA.
DR EMBL; AF001294; AAB86680.1; -; mRNA.
DR EMBL; AF035444; AAC17458.1; -; mRNA.
DR EMBL; CR407664; CAG28592.1; -; mRNA.
DR EMBL; AK223027; BAD96747.1; -; mRNA.
DR EMBL; BC005034; AAH05034.1; -; mRNA.
DR CCDS; CCDS7741.1; -.
DR RefSeq; NP_003302.1; NM_003311.3.
DR AlphaFoldDB; Q53GA4; -.
DR SMR; Q53GA4; -.
DR BioGRID; 113113; 14.
DR IntAct; Q53GA4; 8.
DR STRING; 9606.ENSP00000319231; -.
DR iPTMnet; Q53GA4; -.
DR PhosphoSitePlus; Q53GA4; -.
DR BioMuta; PHLDA2; -.
DR DMDM; 84029394; -.
DR EPD; Q53GA4; -.
DR jPOST; Q53GA4; -.
DR MassIVE; Q53GA4; -.
DR MaxQB; Q53GA4; -.
DR PaxDb; Q53GA4; -.
DR PeptideAtlas; Q53GA4; -.
DR PRIDE; Q53GA4; -.
DR ProteomicsDB; 62476; -.
DR Antibodypedia; 1202; 307 antibodies from 33 providers.
DR DNASU; 7262; -.
DR Ensembl; ENST00000314222.5; ENSP00000319231.4; ENSG00000181649.8.
DR Ensembl; ENST00000618418.2; ENSP00000483602.1; ENSG00000274538.2.
DR GeneID; 7262; -.
DR KEGG; hsa:7262; -.
DR MANE-Select; ENST00000314222.5; ENSP00000319231.4; NM_003311.4; NP_003302.1.
DR UCSC; uc001lxa.2; human.
DR CTD; 7262; -.
DR DisGeNET; 7262; -.
DR GeneCards; PHLDA2; -.
DR HGNC; HGNC:12385; PHLDA2.
DR HPA; ENSG00000181649; Tissue enhanced (esophagus, placenta).
DR MIM; 602131; gene.
DR neXtProt; NX_Q53GA4; -.
DR OpenTargets; ENSG00000181649; -.
DR PharmGKB; PA37053; -.
DR VEuPathDB; HostDB:ENSG00000181649; -.
DR eggNOG; ENOG502RXZA; Eukaryota.
DR GeneTree; ENSGT00440000039564; -.
DR HOGENOM; CLU_062639_1_0_1; -.
DR InParanoid; Q53GA4; -.
DR OMA; DNCWNAV; -.
DR OrthoDB; 1412115at2759; -.
DR PhylomeDB; Q53GA4; -.
DR TreeFam; TF332320; -.
DR PathwayCommons; Q53GA4; -.
DR SignaLink; Q53GA4; -.
DR BioGRID-ORCS; 7262; 20 hits in 1079 CRISPR screens.
DR ChiTaRS; PHLDA2; human.
DR GeneWiki; PHLDA2; -.
DR GenomeRNAi; 7262; -.
DR Pharos; Q53GA4; Tbio.
DR PRO; PR:Q53GA4; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; Q53GA4; protein.
DR Bgee; ENSG00000181649; Expressed in placenta and 89 other tissues.
DR Genevisible; Q53GA4; HS.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR GO; GO:1901981; F:phosphatidylinositol phosphate binding; IEA:InterPro.
DR GO; GO:0009887; P:animal organ morphogenesis; IEA:Ensembl.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0001890; P:placenta development; IBA:GO_Central.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:InterPro.
DR GO; GO:0030334; P:regulation of cell migration; IEA:Ensembl.
DR GO; GO:0045995; P:regulation of embryonic development; IEA:Ensembl.
DR GO; GO:0010468; P:regulation of gene expression; IEA:Ensembl.
DR GO; GO:0070873; P:regulation of glycogen metabolic process; IEA:Ensembl.
DR GO; GO:1903547; P:regulation of growth hormone activity; IEA:Ensembl.
DR GO; GO:0060721; P:regulation of spongiotrophoblast cell proliferation; IEA:Ensembl.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR InterPro; IPR042832; PHLA1/2/3.
DR PANTHER; PTHR15478; PTHR15478; 1.
DR SMART; SM00233; PH; 1.
PE 1: Evidence at protein level;
KW Cytoplasm; Membrane; Phosphoprotein; Reference proteome.
FT CHAIN 1..152
FT /note="Pleckstrin homology-like domain family A member 2"
FT /id="PRO_0000053900"
FT DOMAIN 7..99
FT /note="PH"
FT REGION 112..152
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 138..152
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 3
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 42
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"
FT MOD_RES 141
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976"
FT MOD_RES 144
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:18691976"
FT MOD_RES 151
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT CONFLICT 24
FT /note="W -> R (in Ref. 5; BAD96747)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 152 AA; 17092 MW; 3A1168CBB859FC3B CRC64;
MKSPDEVLRE GELEKRSDSL FQLWKKKRGV LTSDRLSLFP ASPRARPKEL RFHSILKVDC
VERTGKYVYF TIVTTDHKEI DFRCAGESCW NAAIALALID FQNRRALQDF RSRQERTAPA
APAEDAVAAA AAAPSEPSEP SRPSPQPKPR TP
