ID PHLP1_HUMAN Reviewed; 1717 AA. AC O60346; A1A4F5; Q641Q7; Q6P4C4; Q6PJI6; Q86TN6; Q96FK2; Q9NUY1; DT 07-JUN-2005, integrated into UniProtKB/Swiss-Prot. DT 07-JUN-2005, sequence version 3. DT 27-MAR-2024, entry version 203. DE RecName: Full=PH domain leucine-rich repeat-containing protein phosphatase 1; DE EC=3.1.3.16; DE AltName: Full=Pleckstrin homology domain-containing family E member 1; DE Short=PH domain-containing family E member 1; DE AltName: Full=Suprachiasmatic nucleus circadian oscillatory protein; DE Short=hSCOP; GN Name=PHLPP1; Synonyms=KIAA0606, PHLPP, PLEKHE1, SCOP; 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 [LARGE SCALE GENOMIC DNA]. RX PubMed=16177791; DOI=10.1038/nature03983; RA Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D., RA Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., RA Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J., RA Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L., RA Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., RA Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., RA Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K., RA Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R., RA Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.; RT "DNA sequence and analysis of human chromosome 18."; RL Nature 437:551-555(2005). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 349-1717. RC TISSUE=Brain; RX PubMed=9628581; DOI=10.1093/dnares/5.1.31; RA Nagase T., Ishikawa K., Miyajima N., Tanaka A., Kotani H., Nomura N., RA Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. IX. The RT complete sequences of 100 new cDNA clones from brain which can code for RT large proteins in vitro."; RL DNA Res. 5:31-39(1998). RN [3] RP SEQUENCE REVISION. RX PubMed=12168954; DOI=10.1093/dnares/9.3.99; RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.; RT "Construction of expression-ready cDNA clones for KIAA genes: manual RT curation of 330 KIAA cDNA clones."; RL DNA Res. 9:99-106(2002). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 475-1717. RC TISSUE=Cerebellum, Hippocampus, Lymphoma, Melanoma, and RC Retinoblastoma; 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 495-1233. RC TISSUE=Placenta; 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 [6] RP FUNCTION, ENZYME ACTIVITY, COFACTOR, ACTIVITY REGULATION, TISSUE RP SPECIFICITY, AND MUTAGENESIS OF 1715-THR--LEU-1717. RX PubMed=15808505; DOI=10.1016/j.molcel.2005.03.008; RA Gao T., Furnari F., Newton A.C.; RT "PHLPP: a phosphatase that directly dephosphorylates Akt, promotes RT apoptosis, and suppresses tumor growth."; RL Mol. Cell 18:13-24(2005). RN [7] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [8] RP FUNCTION, SUBCELLULAR LOCATION, ALTERNATIVE SPLICING, AND INTERACTION WITH RP AKT2 AND AKT3. RX PubMed=17386267; DOI=10.1016/j.molcel.2007.02.017; RA Brognard J., Sierecki E., Gao T., Newton A.C.; RT "PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude RT of Akt signaling by regulating distinct Akt isoforms."; RL Mol. Cell 25:917-931(2007). RN [9] RP FUNCTION, AND INTERACTION WITH PRKCB. RX PubMed=18162466; DOI=10.1074/jbc.m707319200; RA Gao T., Brognard J., Newton A.C.; RT "The phosphatase PHLPP controls the cellular levels of protein kinase C."; RL J. Biol. Chem. 283:6300-6311(2008). RN [10] RP INTERACTION WITH FKBP5; AKT2 AND AKT3. RX PubMed=19732725; DOI=10.1016/j.ccr.2009.07.016; RA Pei H., Li L., Fridley B.L., Jenkins G.D., Kalari K.R., Lingle W., RA Petersen G., Lou Z., Wang L.; RT "FKBP51 affects cancer cell response to chemotherapy by negatively RT regulating Akt."; RL Cancer Cell 16:259-266(2009). RN [11] RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=19079341; DOI=10.1038/onc.2008.450; RA Liu J., Weiss H.L., Rychahou P., Jackson L.N., Evers B.M., Gao T.; RT "Loss of PHLPP expression in colon cancer: role in proliferation and RT tumorigenesis."; RL Oncogene 28:994-1004(2009). RN [12] RP FUNCTION, AND INTERACTION WITH STK4. RX PubMed=20513427; DOI=10.1016/j.molcel.2010.03.017; RA Qiao M., Wang Y., Xu X., Lu J., Dong Y., Tao W., Stein J., Stein G.S., RA Iglehart J.D., Shi Q., Pardee A.B.; RT "Mst1 is an interacting protein that mediates PHLPPs' induced apoptosis."; RL Mol. Cell 38:512-523(2010). RN [13] RP INTERACTION WITH SCRIB. RX PubMed=21701506; DOI=10.1038/embor.2011.106; RA Li X., Yang H., Liu J., Schmidt M.D., Gao T.; RT "Scribble-mediated membrane targeting of PHLPP1 is required for its RT negative regulation of Akt."; RL EMBO Rep. 12:818-824(2011). RN [14] RP FUNCTION, AND INTERACTION WITH RPS6KB1. RX PubMed=21986499; DOI=10.1128/mcb.05799-11; RA Liu J., Stevens P.D., Li X., Schmidt M.D., Gao T.; RT "PHLPP-mediated dephosphorylation of S6K1 inhibits protein translation and RT cell growth."; RL Mol. Cell. Biol. 31:4917-4927(2011). RN [15] RP INTERACTION WITH NHERF1. RX PubMed=21804599; DOI=10.1038/onc.2011.324; RA Molina J.R., Agarwal N.K., Morales F.C., Hayashi Y., Aldape K.D., Cote G., RA Georgescu M.M.; RT "PTEN, NHERF1 and PHLPP form a tumor suppressor network that is disabled in RT glioblastoma."; RL Oncogene 31:1264-1274(2012). RN [16] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP 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 [17] RP INTERACTION WITH WDR48 AND USP12, AND ACTIVITY REGULATION. RX PubMed=24145035; DOI=10.1074/jbc.m113.503383; RA Gangula N.R., Maddika S.; RT "WD repeat protein WDR48 in complex with deubiquitinase USP12 suppresses RT Akt-dependent cell survival signaling by stabilizing PH domain leucine-rich RT repeat protein phosphatase 1 (PHLPP1)."; RL J. Biol. Chem. 288:34545-34554(2013). RN [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-317 AND SER-412, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; 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). RN [19] RP CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND COFACTOR. RX PubMed=24892992; DOI=10.1021/bi500428j; RA Sierecki E., Newton A.C.; RT "Biochemical characterization of the phosphatase domain of the tumor RT suppressor PH domain leucine-rich repeat protein phosphatase."; RL Biochemistry 53:3971-3981(2014). RN [20] RP FUNCTION, AND INTERACTION WITH RAF1. RX PubMed=24530606; DOI=10.1053/j.gastro.2014.02.003; RA Li X., Stevens P.D., Liu J., Yang H., Wang W., Wang C., Zeng Z., RA Schmidt M.D., Yang M., Lee E.Y., Gao T.; RT "PHLPP is a negative regulator of RAF1, which reduces colorectal cancer RT cell motility and prevents tumor progression in mice."; RL Gastroenterology 146:1301-1310(2014). RN [21] RP INTERACTION WITH BRAP. RX PubMed=25820252; DOI=10.1038/srep09459; RA Fatima S., Wagstaff K.M., Loveland K.L., Jans D.A.; RT "Interactome of the negative regulator of nuclear import BRCA1-binding RT protein 2."; RL Sci. Rep. 5:9459-9459(2015). CC -!- FUNCTION: Protein phosphatase involved in regulation of Akt and PKC CC signaling. Mediates dephosphorylation in the C-terminal domain CC hydrophobic motif of members of the AGC Ser/Thr protein kinase family; CC specifically acts on 'Ser-473' of AKT2 and AKT3, 'Ser-660' of PRKCB and CC 'Ser-657' of PRKCA (PubMed:15808505, PubMed:17386267, PubMed:18162466). CC Isoform 2 seems to have a major role in regulating Akt signaling in CC hippocampal neurons (By similarity). Akt regulates the balance between CC cell survival and apoptosis through a cascade that primarily alters the CC function of transcription factors that regulate pro- and antiapoptotic CC genes. Dephosphorylation of 'Ser-473' of Akt triggers apoptosis and CC suppression of tumor growth. Dephosphorylation of PRKCA and PRKCB leads CC to their destabilization and degradation (PubMed:18162466). CC Dephosphorylates STK4 on 'Thr-387' leading to STK4 activation and CC apoptosis (PubMed:20513427). Dephosphorylates RPS6KB1 and is involved CC in regulation of cap-dependent translation (PubMed:21986499). Inhibits CC cancer cell proliferation and may act as a tumor suppressor CC (PubMed:19079341). Dephosphorylates RAF1 inhibiting its kinase activity CC (PubMed:24530606). May act as a negative regulator of K-Ras signaling CC in membrane rafts (By similarity). Involved in the hippocampus- CC dependent long-term memory formation (By similarity). Involved in CC circadian control by regulating the consolidation of circadian CC periodicity after resetting (By similarity). Involved in development CC and function of regulatory T-cells (By similarity). CC {ECO:0000250|UniProtKB:Q8CHE4, ECO:0000250|UniProtKB:Q9WTR8, CC ECO:0000269|PubMed:15808505, ECO:0000269|PubMed:17386267, CC ECO:0000269|PubMed:18162466, ECO:0000269|PubMed:19079341, CC ECO:0000269|PubMed:21986499, ECO:0000269|PubMed:24530606}. CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + O-phospho-L-seryl-[protein] = L-seryl-[protein] + CC phosphate; Xref=Rhea:RHEA:20629, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:43474, CC ChEBI:CHEBI:83421; EC=3.1.3.16; CC Evidence={ECO:0000269|PubMed:15808505, ECO:0000269|PubMed:24892992}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + O-phospho-L-threonyl-[protein] = L-threonyl-[protein] + CC phosphate; Xref=Rhea:RHEA:47004, Rhea:RHEA-COMP:11060, Rhea:RHEA- CC COMP:11605, ChEBI:CHEBI:15377, ChEBI:CHEBI:30013, ChEBI:CHEBI:43474, CC ChEBI:CHEBI:61977; EC=3.1.3.16; CC Evidence={ECO:0000269|PubMed:15808505, ECO:0000269|PubMed:24892992}; CC -!- COFACTOR: CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000250}; CC Note=Binds 2 manganese ions per subunit (By similarity). Mn(2+) is CC inhibitory below pH 8 and activating above pH 8 (PubMed:24892992). CC {ECO:0000250, ECO:0000269|PubMed:24892992}; CC -!- ACTIVITY REGULATION: Insensitive to okadaic acid (PubMed:15808505). CC Deubiquitination by WDR48-USP12 complex positively regulates PHLPP1 CC stability (PubMed:24145035). {ECO:0000269|PubMed:15808505, CC ECO:0000269|PubMed:24145035}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=1.5 mM for p-nitrophenyl phosphate {ECO:0000269|PubMed:24892992}; CC -!- SUBUNIT: Interacts with the nucleotide free form of K-Ras (KRAS) via CC its LRR repeats (By similarity). Interacts with AKT2, AKT3, PRKCB CC isoform beta-II, STK4, RPS6KB1, RAF1 (PubMed:17386267, PubMed:18162466, CC PubMed:19732725, PubMed:21986499, PubMed:24530606). Isoform 1 CC (predominantly) and isoform 2 interact with BRAP (PubMed:25820252). CC Interacts with FKBP5; FKBP5 acts as a scaffold for PHLPP1 and Akt CC (PubMed:19732725). Interacts with SCRIB; SCRIB acts as a scaffold for CC PHLPP1 and Akt (PubMed:21701506). Interacts with NHERF1; NHERF1 CC scaffolds a heterotrimeric complex with PTEN at the plasma membrane CC (PubMed:21804599). Interacts with WDR48 and USP12 (PubMed:24145035). CC {ECO:0000250|UniProtKB:Q9WTR8, ECO:0000269|PubMed:17386267, CC ECO:0000269|PubMed:18162466, ECO:0000269|PubMed:19732725, CC ECO:0000269|PubMed:20513427, ECO:0000269|PubMed:21701506, CC ECO:0000269|PubMed:21804599, ECO:0000269|PubMed:21986499, CC ECO:0000269|PubMed:24145035, ECO:0000269|PubMed:24530606, CC ECO:0000269|PubMed:25820252}. CC -!- INTERACTION: CC O60346; O14745: NHERF1; NbExp=2; IntAct=EBI-2511516, EBI-349787; CC O60346; P05771-2: PRKCB; NbExp=5; IntAct=EBI-2511516, EBI-5774511; CC O60346; Q14160: SCRIB; NbExp=2; IntAct=EBI-2511516, EBI-357345; CC O60346; Q80U72: Scrib; Xeno; NbExp=2; IntAct=EBI-2511516, EBI-1766028; CC O60346-2; O14745: NHERF1; NbExp=5; IntAct=EBI-11165225, EBI-349787; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Membrane; Peripheral membrane protein. CC Nucleus. Note=In colorectal cancer tissue, expression is concentrated CC at the lateral membrane of epithelial cells. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cell membrane CC {ECO:0000269|PubMed:21804599}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; Synonyms=beta; CC IsoId=O60346-1; Sequence=Displayed; CC Name=2; Synonyms=alpha; CC IsoId=O60346-2; Sequence=VSP_057809; CC -!- TISSUE SPECIFICITY: In colorectal cancer tissue, expression is highest CC in the surface epithelium of normal colonic mucosa adjacent to the CC cancer tissue but is largely excluded from the crypt bases. Expression CC is lost or significantly decreased in 78% of tested tumors (at protein CC level). Ubiquitously expressed in non-cancerous tissues. CC {ECO:0000269|PubMed:15808505, ECO:0000269|PubMed:19079341}. CC -!- DOMAIN: The PH domain is required for interaction with PRKCB and its CC dephosphorylation. CC -!- SEQUENCE CAUTION: CC Sequence=AAH14927.3; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH82244.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; CC Sequence=AAI26278.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAA91980.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/44544/PHLPP1"; 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; AC015989; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC022046; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC027553; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AB011178; BAA25532.2; -; mRNA. DR EMBL; BC010706; AAH10706.1; -; mRNA. DR EMBL; BC014927; AAH14927.3; ALT_INIT; mRNA. DR EMBL; BC047653; AAH47653.1; -; mRNA. DR EMBL; BC063519; AAH63519.1; -; mRNA. DR EMBL; BC082244; AAH82244.1; ALT_SEQ; mRNA. DR EMBL; BC126277; AAI26278.1; ALT_INIT; mRNA. DR EMBL; AK001924; BAA91980.1; ALT_INIT; mRNA. DR CCDS; CCDS45881.2; -. [O60346-1] DR PIR; T00258; T00258. DR RefSeq; NP_919431.2; NM_194449.3. [O60346-1] DR AlphaFoldDB; O60346; -. DR SMR; O60346; -. DR BioGRID; 116843; 310. DR CORUM; O60346; -. DR IntAct; O60346; 50. DR MINT; O60346; -. DR STRING; 9606.ENSP00000262719; -. DR BindingDB; O60346; -. DR ChEMBL; CHEMBL3414405; -. DR DEPOD; PHLPP1; -. DR GlyCosmos; O60346; 1 site, 1 glycan. DR GlyGen; O60346; 3 sites, 2 O-linked glycans (3 sites). DR iPTMnet; O60346; -. DR PhosphoSitePlus; O60346; -. DR BioMuta; PHLPP1; -. DR EPD; O60346; -. DR jPOST; O60346; -. DR MassIVE; O60346; -. DR MaxQB; O60346; -. DR PaxDb; 9606-ENSP00000262719; -. DR PeptideAtlas; O60346; -. DR ProteomicsDB; 49376; -. DR Pumba; O60346; -. DR Antibodypedia; 23071; 197 antibodies from 34 providers. DR DNASU; 23239; -. DR Ensembl; ENST00000262719.10; ENSP00000262719.4; ENSG00000081913.14. [O60346-1] DR GeneID; 23239; -. DR KEGG; hsa:23239; -. DR MANE-Select; ENST00000262719.10; ENSP00000262719.4; NM_194449.4; NP_919431.2. DR UCSC; uc021ule.2; human. [O60346-1] DR AGR; HGNC:20610; -. DR CTD; 23239; -. DR DisGeNET; 23239; -. DR GeneCards; PHLPP1; -. DR HGNC; HGNC:20610; PHLPP1. DR HPA; ENSG00000081913; Tissue enhanced (brain). DR MIM; 609396; gene. DR neXtProt; NX_O60346; -. DR OpenTargets; ENSG00000081913; -. DR PharmGKB; PA165429055; -. DR VEuPathDB; HostDB:ENSG00000081913; -. DR eggNOG; KOG0618; Eukaryota. DR GeneTree; ENSGT00940000158137; -. DR HOGENOM; CLU_003020_0_0_1; -. DR InParanoid; O60346; -. DR OMA; GHNQICD; -. DR OrthoDB; 3677323at2759; -. DR PhylomeDB; O60346; -. DR TreeFam; TF315993; -. DR PathwayCommons; O60346; -. DR Reactome; R-HSA-199418; Negative regulation of the PI3K/AKT network. DR SABIO-RK; O60346; -. DR SignaLink; O60346; -. DR SIGNOR; O60346; -. DR BioGRID-ORCS; 23239; 7 hits in 1180 CRISPR screens. DR ChiTaRS; PHLPP1; human. DR GeneWiki; PHLPP_(gene); -. DR GenomeRNAi; 23239; -. DR Pharos; O60346; Tchem. DR PRO; PR:O60346; -. DR Proteomes; UP000005640; Chromosome 18. DR RNAct; O60346; Protein. DR Bgee; ENSG00000081913; Expressed in corpus callosum and 189 other cell types or tissues. DR ExpressionAtlas; O60346; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0017018; F:myosin phosphatase activity; IEA:UniProtKB-EC. DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; IBA:GO_Central. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0009649; P:entrainment of circadian clock; IEA:Ensembl. DR GO; GO:0051898; P:negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IMP:UniProtKB. DR GO; GO:0042981; P:regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:0046328; P:regulation of JNK cascade; IDA:UniProtKB. DR GO; GO:0043408; P:regulation of MAPK cascade; IMP:UniProtKB. DR GO; GO:1900744; P:regulation of p38MAPK cascade; IDA:UniProtKB. DR GO; GO:0002667; P:regulation of T cell anergy; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; IBA:GO_Central. DR CDD; cd13322; PH_PHLPP-like; 1. DR CDD; cd00143; PP2Cc; 1. DR CDD; cd17240; RA_PHLPP1; 1. DR Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 1. DR Gene3D; 3.60.40.10; PPM-type phosphatase domain; 1. DR Gene3D; 3.80.10.10; Ribonuclease Inhibitor; 4. DR InterPro; IPR001611; Leu-rich_rpt. DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp. DR InterPro; IPR032675; LRR_dom_sf. DR InterPro; IPR011993; PH-like_dom_sf. DR InterPro; IPR001849; PH_domain. DR InterPro; IPR036457; PPM-type-like_dom_sf. DR InterPro; IPR001932; PPM-type_phosphatase-like_dom. DR PANTHER; PTHR48051; -; 1. DR PANTHER; PTHR48051:SF37; PH DOMAIN AND LEUCINE-RICH REPEAT PROTEIN PHOSPHATASE 2; 1. DR Pfam; PF13516; LRR_6; 2. DR Pfam; PF13855; LRR_8; 2. DR Pfam; PF00169; PH; 1. DR Pfam; PF00481; PP2C; 1. DR SMART; SM00364; LRR_BAC; 10. DR SMART; SM00369; LRR_TYP; 10. DR SMART; SM00332; PP2Cc; 1. DR SUPFAM; SSF52058; L domain-like; 2. DR SUPFAM; SSF50729; PH domain-like; 1. DR SUPFAM; SSF81606; PP2C-like; 1. DR PROSITE; PS51450; LRR; 17. DR PROSITE; PS50003; PH_DOMAIN; 1. DR PROSITE; PS51746; PPM_2; 1. DR Genevisible; O60346; HS. PE 1: Evidence at protein level; KW Acetylation; Alternative splicing; Apoptosis; Cell membrane; Cytoplasm; KW Hydrolase; Leucine-rich repeat; Manganese; Membrane; Metal-binding; KW Nucleus; Phosphoprotein; Protein phosphatase; Reference proteome; Repeat; KW Tumor suppressor. FT CHAIN 1..1717 FT /note="PH domain leucine-rich repeat-containing protein FT phosphatase 1" FT /id="PRO_0000057781" FT DOMAIN 536..636 FT /note="PH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145" FT REPEAT 638..659 FT /note="LRR 1" FT REPEAT 661..682 FT /note="LRR 2" FT REPEAT 692..712 FT /note="LRR 3" FT REPEAT 715..736 FT /note="LRR 4" FT REPEAT 738..760 FT /note="LRR 5" FT REPEAT 761..783 FT /note="LRR 6" FT REPEAT 784..804 FT /note="LRR 7" FT REPEAT 808..831 FT /note="LRR 8" FT REPEAT 832..853 FT /note="LRR 9" FT REPEAT 873..894 FT /note="LRR 10" FT REPEAT 895..916 FT /note="LRR 11" FT REPEAT 918..939 FT /note="LRR 12" FT REPEAT 941..962 FT /note="LRR 13" FT REPEAT 963..984 FT /note="LRR 14" FT REPEAT 987..1008 FT /note="LRR 15" FT REPEAT 1013..1033 FT /note="LRR 16" FT REPEAT 1037..1058 FT /note="LRR 17" FT REPEAT 1061..1082 FT /note="LRR 18" FT REPEAT 1084..1105 FT /note="LRR 19" FT REPEAT 1106..1127 FT /note="LRR 20" FT REPEAT 1129..1150 FT /note="LRR 21" FT DOMAIN 1175..1422 FT /note="PPM-type phosphatase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01082" FT REGION 1..25 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 41..118 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 136..156 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 252..470 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1076..1205 FT /note="Interaction with NHERF1" FT /evidence="ECO:0000269|PubMed:21804599" FT REGION 1458..1510 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1673..1717 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 1715..1717 FT /note="PDZ-binding; required for interaction with NHERF1" FT /evidence="ECO:0000269|PubMed:21804599" FT COMPBIAS 258..281 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 288..305 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 346..381 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 393..410 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1464..1494 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 1210 FT /ligand="Mn(2+)" FT /ligand_id="ChEBI:CHEBI:29035" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P35813" FT BINDING 1210 FT /ligand="Mn(2+)" FT /ligand_id="ChEBI:CHEBI:29035" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P35813" FT BINDING 1211 FT /ligand="Mn(2+)" FT /ligand_id="ChEBI:CHEBI:29035" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P35813" FT BINDING 1374 FT /ligand="Mn(2+)" FT /ligand_id="ChEBI:CHEBI:29035" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P35813" FT BINDING 1413 FT /ligand="Mn(2+)" FT /ligand_id="ChEBI:CHEBI:29035" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P35813" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES 317 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 412 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT VAR_SEQ 1..512 FT /note="Missing (in isoform 2)" FT /id="VSP_057809" FT VARIANT 1118 FT /note="S -> T (in dbSNP:rs9950585)" FT /id="VAR_056725" FT MUTAGEN 1715..1717 FT /note="Missing: Loss of function in vivo, but does not FT abolishes intrinsic phosphatase activity." FT /evidence="ECO:0000269|PubMed:15808505" FT CONFLICT 691 FT /note="T -> A (in Ref. 5; BAA91980)" FT /evidence="ECO:0000305" FT CONFLICT 1062 FT /note="L -> F (in Ref. 4; AAH47653)" FT /evidence="ECO:0000305" FT CONFLICT 1083 FT /note="R -> S (in Ref. 2; BAA25532)" FT /evidence="ECO:0000305" FT CONFLICT 1227 FT /note="D -> V (in Ref. 5; BAA91980)" FT /evidence="ECO:0000305" FT CONFLICT 1490 FT /note="V -> M (in Ref. 4; AAH47653)" FT /evidence="ECO:0000305" FT CONFLICT 1580 FT /note="Missing (in Ref. 4; AAH63519)" FT /evidence="ECO:0000305" SQ SEQUENCE 1717 AA; 184672 MW; A4AB53F334EA8AB6 CRC64; MEPAAAATVQ RLPELGREDR ASAPAAAAAA AAAAAAAAAA LAAAAGGGRS PEPALTPAAP SGGNGSGSGA REEAPGEAPP GPLPGRAGGA GRRRRRGAPQ PIAGGAAPVP GAGGGANSLL LRRGRLKRNL SAAAAAASSS SSSSAAAASH SPGAAGLPAS CSASASLCTR SLDRKTLLLK HRQTLQLQPS DRDWVRHQLQ RGCVHVFDRH MASTYLRPVL CTLDTTAGEV AARLLQLGHK GGGVVKVLGQ GPGAAAAREP AEPPPEAGPR LAPPEPRDSE VPPARSAPGA FGGPPRAPPA DLPLPVGGPG GWSRRASPAP SDSSPGEPFV GGPVSSPRAP RPVVSDTESF SLSPSAESVS DRLDPYSSGG GSSSSSEELE ADAASAPTGV PGQPRRPGHP AQPLPLPQTA SSPQPQQKAP RAIDSPGGAV REGSCEEKAA AAVAPGGLQS TPGRSGVTAE KAPPPPPPPT LYVQLHGETT RRLEAEEKPL QIQNDYLFQL GFGELWRVQE EGMDSEIGCL IRFYAGKPHS TGSSERIQLS GMYNVRKGKM QLPVNRWTRR QVILCGTCLI VSSVKDSLTG KMHVLPLIGG KVEEVKKHQH CLAFSSSGPQ SQTYYICFDT FTEYLRWLRQ VSKVASQRIS SVDLSCCSLE HLPANLFYSQ DLTHLNLKQN FLRQNPSLPA ARGLNELQRF TKLKSLNLSN NHLGDFPLAV CSIPTLAELN VSCNALRSVP AAVGVMHNLQ TFLLDGNFLQ SLPAELENMK QLSYLGLSFN EFTDIPEVLE KLTAVDKLCM SGNCVETLRL QALRKMPHIK HVDLRLNVIR KLIADEVDFL QHVTQLDLRD NKLGDLDAMI FNNIEVLHCE RNQLVTLDIC GYFLKALYAS SNELVQLDVY PVPNYLSYMD VSRNRLENVP EWVCESRKLE VLDIGHNQIC ELPARLFCNS SLRKLLAGHN QLARLPERLE RTSVEVLDVQ HNQLLELPPN LLMKADSLRF LNASANKLES LPPATLSEET NSILQELYLT NNSLTDKCVP LLTGHPHLKI LHMAYNRLQS FPASKMAKLE ELEEIDLSGN KLKAIPTTIM NCRRMHTVIA HSNCIEVFPE VMQLPEIKCV DLSCNELSEV TLPENLPPKL QELDLTGNPR LVLDHKTLEL LNNIRCFKID QPSTGDASGA PAVWSHGYTE ASGVKNKLCV AALSVNNFCD NREALYGVFD GDRNVEVPYL LQCTMSDILA EELQKTKNEE EYMVNTFIVM QRKLGTAGQK LGGAAVLCHI KHDPVDPGGS FTLTSANVGK CQTVLCRNGK PLPLSRSYIM SCEEELKRIK QHKAIITEDG KVNGVTESTR ILGYTFLHPS VVPRPHVQSV LLTPQDEFFI LGSKGLWDSL SVEEAVEAVR NVPDALAAAK KLCTLAQSYG CHDSISAVVV QLSVTEDSFC CCELSAGGAV PPPSPGIFPP SVNMVIKDRP SDGLGVPSSS SGMASEISSE LSTSEMSSEV GSTASDEPPP GALSENSPAY PSEQRCMLHP ICLSNSFQRQ LSSATFSSAF SDNGLDSDDE EPIEGVFTNG SRVEVEVDIH CSRAKEKEKQ QHLLQVPAEA SDEGIVISAN EDEPGLPRKA DFSAVGTIGR RRANGSVAPQ ERSHNVIEVA TDAPLRKPGG YFAAPAQPDP DDQFIIPPEL EEEVKEIMKH HQEQQQQQQP PPPPQLQPQL PRHYQLDQLP DYYDTPL //