PHLA3_HUMAN
ID PHLA3_HUMAN Reviewed; 127 AA.
AC Q9Y5J5; B2R5A4; Q53HD6; Q8NBW9;
DT 20-DEC-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=Pleckstrin homology-like domain family A member 3;
DE AltName: Full=TDAG51/Ipl homolog 1;
GN Name=PHLDA3; Synonyms=TIH1;
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], AND 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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta, and Thalamus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cerebellum;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and 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 [6]
RP INDUCTION BY TP53.
RX PubMed=15940259; DOI=10.1038/sj.onc.1208755;
RA Kerley-Hamilton J.S., Pike A.M., Li N., DiRenzo J., Spinella M.J.;
RT "A p53-dominant transcriptional response to cisplatin in testicular germ
RT cell tumor-derived human embryonal carcinoma.";
RL Oncogene 24:6090-6100(2005).
RN [7]
RP FUNCTION, PHOSPHOINOSITIDE-BINDING, SUBCELLULAR LOCATION, AND INDUCTION BY
RP 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 [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
CC -!- FUNCTION: p53/TP53-regulated repressor of Akt/AKT1 signaling. Represses
CC AKT1 by preventing AKT1-binding to membrane lipids, thereby inhibiting
CC AKT1 translocation to the cellular membrane and activation. Contributes
CC to p53/TP53-dependent apoptosis by repressing AKT1 activity. Its direct
CC transcription regulation by p53/TP53 may explain how p53/TP53 can
CC negatively regulate AKT1. May act as a tumor suppressor.
CC {ECO:0000269|PubMed:19203586}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19203586}. Membrane
CC {ECO:0000269|PubMed:19203586}; Peripheral membrane protein
CC {ECO:0000269|PubMed:19203586}.
CC -!- TISSUE SPECIFICITY: Widely expressed with lowest expression in liver
CC and spleen. {ECO:0000269|PubMed:10594239}.
CC -!- INDUCTION: By p53/TP53; expression is directly activated by TP53. TP53
CC phosphorylation on 'Ser-15' is required to activate the PHLDA3
CC promoter. {ECO:0000269|PubMed:15940259, ECO:0000269|PubMed:19203586}.
CC -!- DOMAIN: The PH domain binds phosphoinositides with a broad specificity.
CC It competes with the PH domain of AKT1 and directly interferes with
CC AKT1 binding to phosphatidylinositol 4,5-bisphosphate (PIP2) and
CC phosphatidylinositol 3,4,5-trisphosphate (PIP3), preventing AKT1
CC association to membrane lipids and subsequent activation of AKT1
CC signaling.
CC -!- MISCELLANEOUS: PHLDA3 genomic locus is frequently observed in primary
CC lung cancers, suggesting a role in tumor suppression.
CC -!- SIMILARITY: Belongs to the PHLDA3 family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AF151100; AAD42081.1; -; mRNA.
DR EMBL; AK075179; BAC11454.1; -; mRNA.
DR EMBL; AK312115; BAG35051.1; -; mRNA.
DR EMBL; AK222644; BAD96364.1; -; mRNA.
DR EMBL; CH471067; EAW91369.1; -; Genomic_DNA.
DR EMBL; BC014390; AAH14390.1; -; mRNA.
DR EMBL; BC068273; AAH68273.1; -; mRNA.
DR CCDS; CCDS1412.1; -.
DR RefSeq; NP_036528.1; NM_012396.4.
DR AlphaFoldDB; Q9Y5J5; -.
DR SMR; Q9Y5J5; -.
DR BioGRID; 117145; 27.
DR IntAct; Q9Y5J5; 1.
DR STRING; 9606.ENSP00000356280; -.
DR iPTMnet; Q9Y5J5; -.
DR PhosphoSitePlus; Q9Y5J5; -.
DR BioMuta; PHLDA3; -.
DR DMDM; 74735291; -.
DR EPD; Q9Y5J5; -.
DR jPOST; Q9Y5J5; -.
DR MassIVE; Q9Y5J5; -.
DR MaxQB; Q9Y5J5; -.
DR PaxDb; Q9Y5J5; -.
DR PeptideAtlas; Q9Y5J5; -.
DR PRIDE; Q9Y5J5; -.
DR ProteomicsDB; 86420; -.
DR Antibodypedia; 34503; 163 antibodies from 31 providers.
DR DNASU; 23612; -.
DR Ensembl; ENST00000367309.1; ENSP00000356278.1; ENSG00000174307.7.
DR Ensembl; ENST00000367311.5; ENSP00000356280.3; ENSG00000174307.7.
DR GeneID; 23612; -.
DR KEGG; hsa:23612; -.
DR MANE-Select; ENST00000367311.5; ENSP00000356280.3; NM_012396.5; NP_036528.1.
DR UCSC; uc001gwq.5; human.
DR CTD; 23612; -.
DR DisGeNET; 23612; -.
DR GeneCards; PHLDA3; -.
DR HGNC; HGNC:8934; PHLDA3.
DR HPA; ENSG00000174307; Low tissue specificity.
DR MIM; 607054; gene.
DR neXtProt; NX_Q9Y5J5; -.
DR OpenTargets; ENSG00000174307; -.
DR PharmGKB; PA33275; -.
DR VEuPathDB; HostDB:ENSG00000174307; -.
DR eggNOG; ENOG502S2UN; Eukaryota.
DR GeneTree; ENSGT00440000039564; -.
DR HOGENOM; CLU_062639_1_0_1; -.
DR InParanoid; Q9Y5J5; -.
DR OMA; TLWNAEI; -.
DR OrthoDB; 1412115at2759; -.
DR PhylomeDB; Q9Y5J5; -.
DR TreeFam; TF332320; -.
DR PathwayCommons; Q9Y5J5; -.
DR SignaLink; Q9Y5J5; -.
DR BioGRID-ORCS; 23612; 12 hits in 1065 CRISPR screens.
DR ChiTaRS; PHLDA3; human.
DR GenomeRNAi; 23612; -.
DR Pharos; Q9Y5J5; Tbio.
DR PRO; PR:Q9Y5J5; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q9Y5J5; protein.
DR Bgee; ENSG00000174307; Expressed in tibial nerve and 149 other tissues.
DR Genevisible; Q9Y5J5; HS.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0005547; F:phosphatidylinositol-3,4,5-trisphosphate binding; IDA:UniProtKB.
DR GO; GO:0043325; F:phosphatidylinositol-3,4-bisphosphate binding; IDA:UniProtKB.
DR GO; GO:0080025; F:phosphatidylinositol-3,5-bisphosphate binding; IDA:UniProtKB.
DR GO; GO:0032266; F:phosphatidylinositol-3-phosphate binding; IDA:UniProtKB.
DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; IDA:UniProtKB.
DR GO; GO:0010314; F:phosphatidylinositol-5-phosphate binding; IDA:UniProtKB.
DR GO; GO:0009653; P:anatomical structure morphogenesis; TAS:ProtInc.
DR GO; GO:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; IDA:UniProtKB.
DR GO; GO:0051898; P:negative regulation of protein kinase B signaling; IDA:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
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 Apoptosis; Cytoplasm; Membrane; Reference proteome; Tumor suppressor.
FT CHAIN 1..127
FT /note="Pleckstrin homology-like domain family A member 3"
FT /id="PRO_0000053902"
FT DOMAIN 8..127
FT /note="PH"
FT VARIANT 28
FT /note="R -> Q (in dbSNP:rs35383942)"
FT /id="VAR_050515"
FT CONFLICT 8
FT /note="T -> A (in Ref. 3; BAD96364)"
FT /evidence="ECO:0000305"
FT CONFLICT 88
FT /note="P -> L (in Ref. 2; BAC11454)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 127 AA; 13891 MW; 35014547F840D115 CRC64;
MTAAATATVL KEGVLEKRSG GLLQLWKRKR CVLTERGLQL FEAKGTGGRP KELSFARIKA
VECVESTGRH IYFTLVTEGG GEIDFRCPLE DPGWNAQITL GLVKFKNQQA IQTVRARQSL
GTGTLVS
