ID PR15A_HUMAN Reviewed; 674 AA. AC O75807; B4DKQ3; Q6IA96; Q9NVU6; DT 26-FEB-2008, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1998, sequence version 1. DT 27-MAR-2024, entry version 160. DE RecName: Full=Protein phosphatase 1 regulatory subunit 15A; DE AltName: Full=Growth arrest and DNA damage-inducible protein GADD34; DE AltName: Full=Myeloid differentiation primary response protein MyD116 homolog; GN Name=PPP1R15A; Synonyms=GADD34; 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] (ISOFORM 1), AND INDUCTION. RX PubMed=9153226; DOI=10.1074/jbc.272.21.13731; RA Hollander M.C., Zhan Q., Bae I., Fornace A.J. Jr.; RT "Mammalian GADD34, an apoptosis- and DNA damage-inducible gene."; RL J. Biol. Chem. 272:13731-13737(1997). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT THR-32. 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 (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANTS RP GLU-277; SER-312; PRO-316; SER-476 AND ALA-597. RC TISSUE=Umbilical cord blood; 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 [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] (ISOFORM 1). RC TISSUE=Brain; 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 FUNCTION. RX PubMed=8139541; DOI=10.1128/mcb.14.4.2361-2371.1994; RA Zhan Q., Lord K.A., Alamo I. Jr., Hollander M.C., Carrier F., Ron D., RA Kohn K.W., Hoffman B., Liebermann D.A., Fornace A.J. Jr.; RT "The gadd and MyD genes define a novel set of mammalian genes encoding RT acidic proteins that synergistically suppress cell growth."; RL Mol. Cell. Biol. 14:2361-2371(1994). RN [7] RP INTERACTION WITH KMT2A/MLL1 AND SMARCB1, AND INDUCTION. RX PubMed=10490642; DOI=10.1128/mcb.19.10.7050; RA Adler H.T., Chinery R., Wu D.Y., Kussick S.J., Payne J.M., RA Fornace A.J. Jr., Tkachuk D.C.; RT "Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and RT associate with the GADD34 and hSNF5/INI1 proteins."; RL Mol. Cell. Biol. 19:7050-7060(1999). RN [8] RP INTERACTION WITH LYN, AND PHOSPHORYLATION. RX PubMed=11517336; DOI=10.1073/pnas.191130798; RA Grishin A.V., Azhipa O., Semenov I., Corey S.J.; RT "Interaction between growth arrest-DNA damage protein 34 and Src kinase Lyn RT negatively regulates genotoxic apoptosis."; RL Proc. Natl. Acad. Sci. U.S.A. 98:10172-10177(2001). RN [9] RP INTERACTION WITH PP1 AND PPP1R1A, AND FUNCTION. RX PubMed=11564868; DOI=10.1128/mcb.21.20.6841-6850.2001; RA Connor J.H., Weiser D.C., Li S., Hallenbeck J.M., Shenolikar S.; RT "Growth arrest and DNA damage-inducible protein GADD34 assembles a novel RT signaling complex containing protein phosphatase 1 and inhibitor 1."; RL Mol. Cell. Biol. 21:6841-6850(2001). RN [10] RP INTERACTION WITH SMARCB1 AND PPP1R1A, AND MUTAGENESIS OF 555-LYS--PHE-558. RX PubMed=12016208; DOI=10.1074/jbc.m200955200; RA Wu D.Y., Tkachuck D.C., Roberson R.S., Schubach W.H.; RT "The human SNF5/INI1 protein facilitates the function of the growth arrest RT and DNA damage-inducible protein (GADD34) and modulates GADD34-bound RT protein phosphatase-1 activity."; RL J. Biol. Chem. 277:27706-27715(2002). RN [11] RP INDUCTION. RX PubMed=12114539; DOI=10.1073/pnas.152327199; RA Sarkar D., Su Z.-Z., Lebedeva I.V., Sauane M., Gopalkrishnan R.V., RA Valerie K., Dent P., Fisher P.B.; RT "mda-7 (IL-24) Mediates selective apoptosis in human melanoma cells by RT inducing the coordinated overexpression of the GADD family of genes by RT means of p38 MAPK."; RL Proc. Natl. Acad. Sci. U.S.A. 99:10054-10059(2002). RN [12] RP FUNCTION. RX PubMed=14635196; DOI=10.1002/jcb.10711; RA Yagi A., Hasegawa Y., Xiao H., Haneda M., Kojima E., Nishikimi A., RA Hasegawa T., Shimokata K., Isobe K.; RT "GADD34 induces p53 phosphorylation and p21/WAF1 transcription."; RL J. Cell. Biochem. 90:1242-1249(2003). RN [13] RP FUNCTION, MUTAGENESIS OF 556-VAL--SER-558; ARG-612; ARG-614 AND ARG-618, RP AND SUBCELLULAR LOCATION. RX PubMed=12556489; DOI=10.1128/mcb.23.4.1292-1303.2003; RA Brush M.H., Weiser D.C., Shenolikar S.; RT "Growth arrest and DNA damage-inducible protein GADD34 targets protein RT phosphatase 1 alpha to the endoplasmic reticulum and promotes RT dephosphorylation of the alpha subunit of eukaryotic translation initiation RT factor 2."; RL Mol. Cell. Biol. 23:1292-1303(2003). RN [14] RP INTERACTION WITH BAG1. RX PubMed=12724406; DOI=10.1128/mcb.23.10.3477-3486.2003; RA Hung W.J., Roberson R.S., Taft J., Wu D.Y.; RT "Human BAG-1 proteins bind to the cellular stress response protein GADD34 RT and interfere with GADD34 functions."; RL Mol. Cell. Biol. 23:3477-3486(2003). RN [15] RP FUNCTION, AND INTERACTION WITH SMAD7. RX PubMed=14718519; DOI=10.1083/jcb.200307151; RA Shi W., Sun C., He B., Xiong W., Shi X., Yao D., Cao X.; RT "GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor."; RL J. Cell Biol. 164:291-300(2004). RN [16] RP INTERACTION WITH PPP1CA. RX PubMed=15705855; DOI=10.1126/science.1101902; RA Boyce M., Bryant K.F., Jousse C., Long K., Harding H.P., Scheuner D., RA Kaufman R.J., Ma D., Coen D.M., Ron D., Yuan J.; RT "A selective inhibitor of eIF2alpha dephosphorylation protects cells from RT ER stress."; RL Science 307:935-939(2005). RN [17] RP INDUCTION. RX PubMed=19131336; DOI=10.1074/jbc.m806735200; RA Lee Y.Y., Cevallos R.C., Jan E.; RT "An upstream open reading frame regulates translation of GADD34 during RT cellular stresses that induce eIF2alpha phosphorylation."; RL J. Biol. Chem. 284:6661-6673(2009). RN [18] RP SUBCELLULAR LOCATION, TOPOLOGY, INTRAMEMBRANE REGION, AND MUTAGENESIS OF RP VAL-25 AND LEU-29. RX PubMed=21518769; DOI=10.1074/jbc.m110.212787; RA Zhou W., Brush M.H., Choy M.S., Shenolikar S.; RT "Association with endoplasmic reticulum promotes proteasomal degradation of RT GADD34 protein."; RL J. Biol. Chem. 286:21687-21696(2011). RN [19] RP PHOSPHORYLATION AT TYR-262; TYR-391; TYR-434 AND TYR-512, UBIQUITINATION, RP AND MUTAGENESIS OF TYR-262. RX PubMed=24092754; DOI=10.1074/jbc.m113.504407; RA Zhou W., Jeyaraman K., Yusoff P., Shenolikar S.; RT "Phosphorylation at tyrosine 262 promotes GADD34 protein turnover."; RL J. Biol. Chem. 288:33146-33155(2013). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-143, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=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). RN [21] RP FUNCTION, INTERACTION WITH NOX4, AND SUBCELLULAR LOCATION. RX PubMed=26742780; DOI=10.15252/embj.201592394; RA Santos C.X., Hafstad A.D., Beretta M., Zhang M., Molenaar C., Kopec J., RA Fotinou D., Murray T.V., Cobb A.M., Martin D., Zeh Silva M., Anilkumar N., RA Schroeder K., Shanahan C.M., Brewer A.C., Brandes R.P., Blanc E., RA Parsons M., Belousov V., Cammack R., Hider R.C., Steiner R.A., Shah A.M.; RT "Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates RT eIF2alpha-mediated stress signaling."; RL EMBO J. 35:319-334(2016). RN [22] RP FUNCTION, AND INDUCTION BY HIV-1 VIRUS. RX PubMed=31778897; DOI=10.1016/j.virol.2019.11.010; RA Ishaq M., Marshall H., Natarajan V.; RT "GADD34 attenuates HIV-1 replication by viral 5'-UTR TAR RNA-mediated RT translational inhibition."; RL Virology 540:119-131(2020). RN [23] RP FUNCTION. RX PubMed=32978159; DOI=10.1126/sciadv.abb0205; RA Gambardella G., Staiano L., Moretti M.N., De Cegli R., Fagnocchi L., RA Di Tullio G., Polletti S., Braccia C., Armirotti A., Zippo A., Ballabio A., RA De Matteis M.A., di Bernardo D.; RT "GADD34 is a modulator of autophagy during starvation."; RL Sci. Adv. 6:0-0(2020). RN [24] RP FUNCTION (MICROBIAL INFECTION), INDUCTION BY ENTEROVIRUS 71, INTERACTION RP WITH ENTEROVIRUS 71 PROTEIN 3CD (MICROBIAL INFECTION), AND SUBCELLULAR RP LOCATION. RX PubMed=34985336; DOI=10.1128/spectrum.01388-21; RA Li H., Li W., Zhang S., Qiu M., Li Z., Lin Y., Tan J., Qiao W.; RT "Enterovirus 71 Activates GADD34 via Precursor 3CD to Promote IRES-Mediated RT Viral Translation."; RL Microbiol. Spectr. 0:0-0(2022). RN [25] {ECO:0007744|PDB:4XPN} RP X-RAY CRYSTALLOGRAPHY (2.29 ANGSTROMS) OF 552-591 IN COMPLEX WITH PPP1CA RP AND EIF2S1, AND FUNCTION. RX PubMed=26095357; DOI=10.1016/j.celrep.2015.05.043; RA Choy M.S., Yusoff P., Lee I.C., Newton J.C., Goh C.W., Page R., RA Shenolikar S., Peti W.; RT "Structural and Functional Analysis of the GADD34:PP1 eIF2alpha RT Phosphatase."; RL Cell Rep. 11:1885-1891(2015). CC -!- FUNCTION: Recruits the serine/threonine-protein phosphatase PPP1CA to CC prevents excessive phosphorylation of the translation initiation factor CC eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis CC initiated by stress-inducible kinases and facilitating recovery of CC cells from stress (PubMed:26742780, PubMed:26095357). Down-regulates CC the TGF-beta signaling pathway by promoting dephosphorylation of TGFB1 CC by PP1 (PubMed:14718519). May promote apoptosis by inducing p53/TP53 CC phosphorylation on 'Ser-15' (PubMed:14635196). Plays an essential role CC in autophagy by tuning translation during starvation, thus enabling CC lysosomal biogenesis and a sustained autophagic flux (PubMed:32978159). CC Acts also a viral restriction factor by attenuating HIV-1 replication CC (PubMed:31778897). Mechanistically, mediates the inhibition of HIV-1 CC TAR RNA-mediated translation (PubMed:31778897). CC {ECO:0000269|PubMed:11564868, ECO:0000269|PubMed:12556489, CC ECO:0000269|PubMed:14635196, ECO:0000269|PubMed:14718519, CC ECO:0000269|PubMed:26095357, ECO:0000269|PubMed:31778897, CC ECO:0000269|PubMed:8139541}. CC -!- FUNCTION: (Microbial infection) Promotes enterovirus 71 replication by CC mediating the internal ribosome entry site (IRES) activity of viral 5'- CC UTR. {ECO:0000269|PubMed:34985336}. CC -!- SUBUNIT: Interacts with PPP1CA (PubMed:15705855, PubMed:26095357). CC Interacts with EIF2S1 (PubMed:26095357). Interacts with PCNA (By CC similarity). Interacts with LYN and KMT2A/MLL1 (PubMed:11517336). CC Interacts with PPP1R1A and SMARCB1 (PubMed:12016208). Interacts with CC SMAD7 (PubMed:14718519). Interacts with BAG1 (PubMed:12724406). CC Interacts with NOX4 (PubMed:26742780). {ECO:0000250, CC ECO:0000269|PubMed:10490642, ECO:0000269|PubMed:11517336, CC ECO:0000269|PubMed:11564868, ECO:0000269|PubMed:12016208, CC ECO:0000269|PubMed:12724406, ECO:0000269|PubMed:14718519, CC ECO:0000269|PubMed:15705855, ECO:0000269|PubMed:26095357, CC ECO:0000269|PubMed:26742780}. CC -!- SUBUNIT: (Microbial infection) Interacts with enterovirus 71/EV71 non- CC structural protein precursor 3CD; this interaction promotes EV71 CC replication. {ECO:0000269|PubMed:34985336}. CC -!- INTERACTION: CC O75807; P56545: CTBP2; NbExp=2; IntAct=EBI-714746, EBI-741533; CC O75807; P62136: PPP1CA; NbExp=12; IntAct=EBI-714746, EBI-357253; CC O75807; Q13522: PPP1R1A; NbExp=4; IntAct=EBI-714746, EBI-1568511; CC O75807; Q13148: TARDBP; NbExp=10; IntAct=EBI-714746, EBI-372899; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Peripheral CC membrane protein; Cytoplasmic side {ECO:0000269|PubMed:12556489, CC ECO:0000269|PubMed:21518769, ECO:0000269|PubMed:26742780}. CC Mitochondrion outer membrane; Peripheral membrane protein; Cytoplasmic CC side {ECO:0000269|PubMed:21518769}. Note=Associates with membranes via CC an N-terminal amphipathic intramembrane region. CC {ECO:0000269|PubMed:21518769}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=O75807-1; Sequence=Displayed; CC Name=2; CC IsoId=O75807-2; Sequence=VSP_057083, VSP_057084; CC -!- INDUCTION: Specifically produced in response to stress: in absence of CC stress, some upstream open reading frame (uORF) of this transcript is CC translated, thereby preventing its translation (PubMed:19131336). By CC methyl methanesulfonate and ionizing irradiation (PubMed:9153226). By CC IL24/interleukin-24 in melanoma cells; which induces apoptosis CC (PubMed:10490642, PubMed:12114539). By viral infection including CC enterovirus 71/EV71 or HIV-1 (PubMed:34985336, PubMed:31778897). CC {ECO:0000269|PubMed:10490642, ECO:0000269|PubMed:12114539, CC ECO:0000269|PubMed:19131336, ECO:0000269|PubMed:34985336, CC ECO:0000269|PubMed:9153226}. CC -!- PTM: Phosphorylated at multiple Ser/Thr residues. Phosphorylated on CC tyrosine by LYN; which impairs its antiproliferative activity. CC Phosphorylation at Tyr-262 enhances proteasomal degradation, this CC position is dephosphorylated by PTPN2. {ECO:0000269|PubMed:11517336, CC ECO:0000269|PubMed:24092754}. CC -!- PTM: Polyubiquitinated. Exhibits a rapid proteasomal degradation with a CC half-life under 1 hour, ubiquitination depends on endoplasmic reticulum CC association. {ECO:0000269|PubMed:24092754}. CC -!- MISCELLANEOUS: The phosphatase activity of the PPP1R15A-PP1 complex CC toward EIF2S1 is specifically inhibited by Salubrinal, a drug that CC protects cells from endoplasmic reticulum stress. CC -!- SIMILARITY: Belongs to the PPP1R15 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; U83981; AAC25631.1; -; mRNA. DR EMBL; CR457259; CAG33540.1; -; mRNA. DR EMBL; AK001361; BAA91649.1; -; mRNA. DR EMBL; AK296668; BAG59265.1; -; mRNA. DR EMBL; CH471177; EAW52409.1; -; Genomic_DNA. DR EMBL; BC003067; AAH03067.1; -; mRNA. DR CCDS; CCDS12738.1; -. [O75807-1] DR RefSeq; NP_055145.3; NM_014330.3. [O75807-1] DR PDB; 4XPN; X-ray; 2.29 A; B/D=552-591. DR PDB; 7NXV; X-ray; 2.55 A; C/E=582-621. DR PDB; 7NZM; EM; 3.96 A; C=553-624. DR PDBsum; 4XPN; -. DR PDBsum; 7NXV; -. DR PDBsum; 7NZM; -. DR AlphaFoldDB; O75807; -. DR SMR; O75807; -. DR BioGRID; 117172; 39. DR IntAct; O75807; 204. DR MINT; O75807; -. DR STRING; 9606.ENSP00000200453; -. DR BindingDB; O75807; -. DR ChEMBL; CHEMBL4630805; -. DR iPTMnet; O75807; -. DR PhosphoSitePlus; O75807; -. DR BioMuta; PPP1R15A; -. DR jPOST; O75807; -. DR MassIVE; O75807; -. DR MaxQB; O75807; -. DR PaxDb; 9606-ENSP00000200453; -. DR PeptideAtlas; O75807; -. DR ProteomicsDB; 50202; -. [O75807-1] DR Antibodypedia; 4340; 376 antibodies from 34 providers. DR DNASU; 23645; -. DR Ensembl; ENST00000200453.6; ENSP00000200453.4; ENSG00000087074.9. [O75807-1] DR GeneID; 23645; -. DR KEGG; hsa:23645; -. DR MANE-Select; ENST00000200453.6; ENSP00000200453.4; NM_014330.5; NP_055145.3. DR UCSC; uc002pky.5; human. [O75807-1] DR AGR; HGNC:14375; -. DR CTD; 23645; -. DR DisGeNET; 23645; -. DR GeneCards; PPP1R15A; -. DR HGNC; HGNC:14375; PPP1R15A. DR HPA; ENSG00000087074; Tissue enhanced (bone). DR MIM; 611048; gene. DR neXtProt; NX_O75807; -. DR OpenTargets; ENSG00000087074; -. DR PharmGKB; PA33632; -. DR VEuPathDB; HostDB:ENSG00000087074; -. DR eggNOG; ENOG502S745; Eukaryota. DR GeneTree; ENSGT00940000154404; -. DR HOGENOM; CLU_028812_0_0_1; -. DR InParanoid; O75807; -. DR OMA; VRAWVYR; -. DR OrthoDB; 2912273at2759; -. DR PhylomeDB; O75807; -. DR TreeFam; TF105547; -. DR PathwayCommons; O75807; -. DR Reactome; R-HSA-2173788; Downregulation of TGF-beta receptor signaling. DR Reactome; R-HSA-9648895; Response of EIF2AK1 (HRI) to heme deficiency. DR SignaLink; O75807; -. DR SIGNOR; O75807; -. DR BioGRID-ORCS; 23645; 28 hits in 1160 CRISPR screens. DR ChiTaRS; PPP1R15A; human. DR GeneWiki; PPP1R15A; -. DR GenomeRNAi; 23645; -. DR Pharos; O75807; Tchem. DR PRO; PR:O75807; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; O75807; Protein. DR Bgee; ENSG00000087074; Expressed in mucosa of stomach and 195 other cell types or tissues. DR ExpressionAtlas; O75807; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:ParkinsonsUK-UCL. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:ParkinsonsUK-UCL. DR GO; GO:0005789; C:endoplasmic reticulum membrane; NAS:ParkinsonsUK-UCL. DR GO; GO:0005794; C:Golgi apparatus; IDA:ParkinsonsUK-UCL. DR GO; GO:0016020; C:membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005739; C:mitochondrion; IDA:ParkinsonsUK-UCL. DR GO; GO:0000164; C:protein phosphatase type 1 complex; IDA:ParkinsonsUK-UCL. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0008157; F:protein phosphatase 1 binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0072542; F:protein phosphatase activator activity; IC:ParkinsonsUK-UCL. DR GO; GO:0019888; F:protein phosphatase regulator activity; IBA:GO_Central. DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc. DR GO; GO:0006974; P:DNA damage response; TAS:ProtInc. DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; TAS:ParkinsonsUK-UCL. DR GO; GO:1903898; P:negative regulation of PERK-mediated unfolded protein response; TAS:ParkinsonsUK-UCL. DR GO; GO:0032515; P:negative regulation of phosphoprotein phosphatase activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0035308; P:negative regulation of protein dephosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:1903917; P:positive regulation of endoplasmic reticulum stress-induced eIF2 alpha dephosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:1902310; P:positive regulation of peptidyl-serine dephosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:0032516; P:positive regulation of phosphoprotein phosphatase activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0032058; P:positive regulation of translational initiation in response to stress; IC:ParkinsonsUK-UCL. DR GO; GO:0070972; P:protein localization to endoplasmic reticulum; IMP:ParkinsonsUK-UCL. DR GO; GO:0051726; P:regulation of cell cycle; TAS:ProtInc. DR GO; GO:0036496; P:regulation of translational initiation by eIF2 alpha dephosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IDA:ParkinsonsUK-UCL. DR DisProt; DP01203; -. DR InterPro; IPR019523; Prot_Pase1_reg-su15A/B_C. DR PANTHER; PTHR16489; GH11727P; 1. DR PANTHER; PTHR16489:SF14; PROTEIN PHOSPHATASE 1 REGULATORY SUBUNIT 15A; 1. DR Pfam; PF10488; PP1c_bdg; 1. DR Genevisible; O75807; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Apoptosis; Endoplasmic reticulum; KW Membrane; Mitochondrion; Mitochondrion outer membrane; Phosphoprotein; KW Reference proteome; Repeat; Stress response; Translation regulation; KW Ubl conjugation. FT CHAIN 1..674 FT /note="Protein phosphatase 1 regulatory subunit 15A" FT /id="PRO_0000320518" FT TOPO_DOM 1..21 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:21518769" FT INTRAMEM 22..39 FT /note="Helical" FT /evidence="ECO:0000305|PubMed:21518769" FT TOPO_DOM 40..674 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:21518769" FT REPEAT 337..369 FT /note="1" FT REPEAT 384..417 FT /note="2" FT REPEAT 427..460 FT /note="3" FT REPEAT 477..510 FT /note="4" FT REGION 1..60 FT /note="Required for localization in the endoplasmic FT reticulum" FT REGION 65..504 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 337..510 FT /note="4 X 34 AA approximate repeats" FT REGION 337..510 FT /note="Interaction with SMAD7" FT /evidence="ECO:0000269|PubMed:14718519" FT REGION 483..555 FT /note="Interaction with KMT2A/MLL1" FT REGION 534..554 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 536..583 FT /note="Interaction with SMARCB1" FT REGION 625..674 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 75..92 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 126..152 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 205..226 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 228..245 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 262..281 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 306..322 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 348..374 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 395..411 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 438..461 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 462..492 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 630..658 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 143 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 262 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:24092754" FT MOD_RES 391 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:24092754" FT MOD_RES 434 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:24092754" FT MOD_RES 512 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:24092754" FT VAR_SEQ 16 FT /note="A -> D (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_057083" FT VAR_SEQ 17..175 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_057084" FT VARIANT 31 FT /note="R -> H (in dbSNP:rs564196)" FT /id="VAR_039186" FT VARIANT 32 FT /note="A -> T (in dbSNP:rs3786734)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_039187" FT VARIANT 199 FT /note="V -> A (in dbSNP:rs611251)" FT /id="VAR_039188" FT VARIANT 251 FT /note="R -> P (in dbSNP:rs557806)" FT /id="VAR_039189" FT VARIANT 277 FT /note="K -> E (in dbSNP:rs610308)" FT /evidence="ECO:0000269|PubMed:14702039" FT /id="VAR_039190" FT VARIANT 312 FT /note="G -> S (in dbSNP:rs11541192)" FT /evidence="ECO:0000269|PubMed:14702039" FT /id="VAR_062226" FT VARIANT 316 FT /note="A -> P (in dbSNP:rs556052)" FT /evidence="ECO:0000269|PubMed:14702039" FT /id="VAR_039191" FT VARIANT 381 FT /note="A -> V (in dbSNP:rs1050166)" FT /id="VAR_039192" FT VARIANT 476 FT /note="R -> S (in dbSNP:rs35087747)" FT /evidence="ECO:0000269|PubMed:14702039" FT /id="VAR_039193" FT VARIANT 594 FT /note="R -> C (in dbSNP:rs2270946)" FT /id="VAR_039194" FT VARIANT 597 FT /note="T -> A (in dbSNP:rs500079)" FT /evidence="ECO:0000269|PubMed:14702039" FT /id="VAR_039195" FT MUTAGEN 25 FT /note="V->R: Localizes to cytoplasm, degraded more slowly." FT /evidence="ECO:0000269|PubMed:21518769" FT MUTAGEN 29 FT /note="L->R: Localizes to cytoplasm." FT /evidence="ECO:0000269|PubMed:21518769" FT MUTAGEN 262 FT /note="Y->F: Significantly reduced turnover." FT /evidence="ECO:0000269|PubMed:24092754" FT MUTAGEN 555..558 FT /note="KVRF->AAAA: Reduces interaction with SMARCB1." FT /evidence="ECO:0000269|PubMed:12016208" FT MUTAGEN 556..558 FT /note="VRF->ARA: Impairs PP1 activation." FT /evidence="ECO:0000269|PubMed:12556489" FT MUTAGEN 612 FT /note="R->K: Reduces PP1-binding; when associated with FT K-614." FT /evidence="ECO:0000269|PubMed:12556489" FT MUTAGEN 614 FT /note="R->K: Reduces PP1-binding; when associated with FT K-612." FT /evidence="ECO:0000269|PubMed:12556489" FT MUTAGEN 618 FT /note="R->D: Reduces PP1-binding." FT /evidence="ECO:0000269|PubMed:12556489" FT CONFLICT 80 FT /note="E -> G (in Ref. 3; BAA91649)" FT /evidence="ECO:0000305" FT CONFLICT 297 FT /note="P -> L (in Ref. 2; CAG33540)" FT /evidence="ECO:0000305" FT CONFLICT 669 FT /note="L -> P (in Ref. 3; BAG59265)" FT /evidence="ECO:0000305" FT STRAND 563..565 FT /evidence="ECO:0007829|PDB:4XPN" FT HELIX 583..602 FT /evidence="ECO:0007829|PDB:7NXV" FT HELIX 604..606 FT /evidence="ECO:0007829|PDB:7NXV" FT HELIX 609..618 FT /evidence="ECO:0007829|PDB:7NXV" SQ SEQUENCE 674 AA; 73478 MW; B257AA17456D1403 CRC64; MAPGQAPHQA TPWRDAHPFF LLSPVMGLLS RAWSRLRGLG PLEPWLVEAV KGAALVEAGL EGEARTPLAI PHTPWGRRPE EEAEDSGGPG EDRETLGLKT SSSLPEAWGL LDDDDGMYGE REATSVPRGQ GSQFADGQRA PLSPSLLIRT LQGSDKNPGE EKAEEEGVAE EEGVNKFSYP PSHRECCPAV EEEDDEEAVK KEAHRTSTSA LSPGSKPSTW VSCPGEEENQ ATEDKRTERS KGARKTSVSP RSSGSDPRSW EYRSGEASEE KEEKAHKETG KGEAAPGPQS SAPAQRPQLK SWWCQPSDEE EGEVKALGAA EKDGEAECPP CIPPPSAFLK AWVYWPGEDT EEEEDEEEDE DSDSGSDEEE GEAEASSSTP ATGVFLKSWV YQPGEDTEEE EDEDSDTGSA EDEREAETSA STPPASAFLK AWVYRPGEDT EEEEDEDVDS EDKEDDSEAA LGEAESDPHP SHPDQRAHFR GWGYRPGKET EEEEAAEDWG EAEPCPFRVA IYVPGEKPPP PWAPPRLPLR LQRRLKRPET PTHDPDPETP LKARKVRFSE KVTVHFLAVW AGPAQAARQG PWEQLARDRS RFARRITQAQ EELSPCLTPA ARARAWARLR NPPLAPIPAL TQTLPSSSVP SSPVQTTPLS QAVATPSRSS AAAAAALDLS GRRG //