ID PR15A_MOUSE Reviewed; 657 AA. AC P17564; Q3TJS6; Q3U3L5; Q8C579; DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot. DT 01-AUG-1990, sequence version 1. DT 02-DEC-2020, entry version 133. 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; GN Name=Ppp1r15a; Synonyms=Gadd34, Myd116; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC STRAIN=SL; RX PubMed=2339071; DOI=10.1093/nar/18.9.2823; RA Lord K.A., Hoffman-Liebermann B., Liebermann D.A.; RT "Sequence of MyD116 cDNA: a novel myeloid differentiation primary response RT gene induced by IL6."; RL Nucleic Acids Res. 18:2823-2823(1990). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC STRAIN=C57BL/6J, and NOD; TISSUE=Cerebellum, and Placenta; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [3] RP INDUCTION. RX PubMed=8139541; DOI=10.1128/mcb.14.4.2361; 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 [4] RP INTERACTION WITH PCNA. RX PubMed=9371605; DOI=10.1128/jvi.71.12.9442-9449.1997; RA Brown S.M., MacLean A.R., McKie E.A., Harland J.; RT "The herpes simplex virus virulence factor ICP34.5 and the cellular protein RT MyD116 complex with proliferating cell nuclear antigen through the 63- RT amino-acid domain conserved in ICP34.5, MyD116, and GADD34."; RL J. Virol. 71:9442-9449(1997). RN [5] RP INTERACTION WITH PP1. RX PubMed=9023344; DOI=10.1073/pnas.94.3.843; RA He B., Gross M., Roizman B.; RT "The gamma(1)34.5 protein of herpes simplex virus 1 complexes with protein RT phosphatase 1alpha to dephosphorylate the alpha subunit of the eukaryotic RT translation initiation factor 2 and preclude the shutoff of protein RT synthesis by double-stranded RNA-activated protein kinase."; RL Proc. Natl. Acad. Sci. U.S.A. 94:843-848(1997). RN [6] RP FUNCTION, INTERACTION WITH PP1, AND MUTAGENESIS OF VAL-549. RX PubMed=11381086; DOI=10.1083/jcb.153.5.1011; RA Novoa I., Zeng H., Harding H.P., Ron D.; RT "Feedback inhibition of the unfolded protein response by GADD34-mediated RT dephosphorylation of eIF2alpha."; RL J. Cell Biol. 153:1011-1022(2001). RN [7] RP INTERACTION WITH LYN. 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 [8] RP INDUCTION, AND FUNCTION. RX PubMed=12606582; DOI=10.1093/emboj/cdg112; RA Novoa I., Zhang Y., Zeng H., Jungreis R., Harding H.P., Ron D.; RT "Stress-induced gene expression requires programmed recovery from RT translational repression."; RL EMBO J. 22:1180-1187(2003). RN [9] RP FUNCTION, INDUCTION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND RP DISRUPTION PHENOTYPE. RX PubMed=12824288; DOI=10.1096/fj.02-1184fje; RA Kojima E., Takeuchi A., Haneda M., Yagi A., Hasegawa T., Yamaki K., RA Takeda K., Akira S., Shimokata K., Isobe K.; RT "The function of GADD34 is a recovery from a shutoff of protein synthesis RT induced by ER stress: elucidation by GADD34-deficient mice."; RL FASEB J. 17:1573-1575(2003). RN [10] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=16478986; DOI=10.1128/mcb.26.5.1644-1653.2006; RA Patterson A.D., Hollander M.C., Miller G.F., Fornace A.J. Jr.; RT "Gadd34 requirement for normal hemoglobin synthesis."; RL Mol. Cell. Biol. 26:1644-1653(2006). RN [11] RP FUNCTION, AND INDUCTION. RX PubMed=17670836; DOI=10.1128/jvi.01063-07; RA Minami K., Tambe Y., Watanabe R., Isono T., Haneda M., Isobe K., RA Kobayashi T., Hino O., Okabe H., Chano T., Inoue H.; RT "Suppression of viral replication by stress-inducible GADD34 protein via RT the mammalian serine/threonine protein kinase mTOR pathway."; RL J. Virol. 81:11106-11115(2007). RN [12] 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). CC -!- FUNCTION: Recruits the serine/threonine-protein phosphatase PP1 to CC dephosphorylate the translation initiation factor eIF-2A/EIF2S1, CC thereby reversing the shut-off of protein synthesis initiated by CC stress-inducible kinases and facilitating recovery of cells from CC stress. Down-regulates the TGF-beta signaling pathway by promoting CC dephosphorylation of TGFB1 by PP1. May promote apoptosis by inducing CC TP53 phosphorylation on 'Ser-15'. In case of infection with vesicular CC stomatitis virus (VSV), impairs viral replication. CC {ECO:0000269|PubMed:11381086, ECO:0000269|PubMed:12606582, CC ECO:0000269|PubMed:12824288, ECO:0000269|PubMed:16478986, CC ECO:0000269|PubMed:17670836}. CC -!- SUBUNIT: Interacts with KMT2A/MLL1. Interacts with SMARCB1. Interacts CC with SMAD7. Interacts with BAG1 (By similarity). Interacts with PCNA. CC Interacts with LYN. Interacts with PP1 and PPP1R1A. {ECO:0000250, CC ECO:0000269|PubMed:11381086, ECO:0000269|PubMed:11517336, CC ECO:0000269|PubMed:9023344, ECO:0000269|PubMed:9371605}. CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Peripheral CC membrane protein; Cytoplasmic side {ECO:0000250|UniProtKB:O75807}. CC Mitochondrion outer membrane; Peripheral membrane protein; Cytoplasmic CC side {ECO:0000250|UniProtKB:O75807}. Note=Associates with membranes via CC an N-terminal amphipathic intramembrane region. CC {ECO:0000250|UniProtKB:O75807}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P17564-1; Sequence=Displayed; CC Name=2; CC IsoId=P17564-2; Sequence=VSP_031651; CC -!- TISSUE SPECIFICITY: Expressed strongly in spleen and lung, moderately CC in thymus and muscle, and weakly in brain. CC {ECO:0000269|PubMed:12824288}. CC -!- DEVELOPMENTAL STAGE: Expression starts at 8.5 dpc, and decreases to CC undetectable levels at 10.5 dpc and 11.5 dpc. Expression is strongly CC up-regulated at 12.5 dpc, decreases at 16.5 dpc and reappears at 18.5 CC dpc. At 12.5 dpc, ubiquitously expressed, with high levels in brain, CC spinal cord, tongue, lung and genital tubercle. CC {ECO:0000269|PubMed:12824288}. 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 IL6 and various endoplasmic stresses such as methyl methanesulfonate CC (PubMed:12606582, PubMed:12824288, PubMed:8139541). CC {ECO:0000269|PubMed:12606582, ECO:0000269|PubMed:12824288, CC ECO:0000269|PubMed:19131336, ECO:0000269|PubMed:8139541}. CC -!- INDUCTION: (Microbial infection) By infection with various viruses such CC as vesicular stomatitis virus (VSV). {ECO:0000269|PubMed:17670836}. CC -!- PTM: Phosphorylated at multiple Ser/Thr residues. Phosphorylated on CC tyrosine by LYN; which impairs its antiproliferative activity. CC Phosphorylation at Tyr-239 enhances proteasomal degradation, this CC position is dephosphorylated by PTPN2. {ECO:0000250|UniProtKB:O75807}. CC -!- PTM: Polyubiquitinated. Exhibits a rapid proteasomal degradation with a CC half-life under 1 hour, ubiquitination depends on endoplasmic reticulum CC association. {ECO:0000250|UniProtKB:O75807}. CC -!- DISRUPTION PHENOTYPE: Mice display abnormal erythrocytes and reduced CC hemoglobin content due to defects in hemoglobin synthesis. CC {ECO:0000269|PubMed:12824288, ECO:0000269|PubMed:16478986}. 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; X51829; CAA36128.1; -; mRNA. DR EMBL; AK079339; BAC37613.1; -; mRNA. DR EMBL; AK154697; BAE32770.1; -; mRNA. DR EMBL; AK167317; BAE39419.1; -; mRNA. DR CCDS; CCDS21249.1; -. [P17564-1] DR PIR; S10001; S10001. DR RefSeq; NP_032680.1; NM_008654.2. [P17564-1] DR SMR; P17564; -. DR BioGRID; 201637; 2. DR STRING; 10090.ENSMUSP00000049488; -. DR iPTMnet; P17564; -. DR PhosphoSitePlus; P17564; -. DR PaxDb; P17564; -. DR PRIDE; P17564; -. DR Antibodypedia; 4340; 277 antibodies. DR Ensembl; ENSMUST00000042105; ENSMUSP00000049488; ENSMUSG00000040435. [P17564-1] DR Ensembl; ENSMUST00000167273; ENSMUSP00000128497; ENSMUSG00000040435. [P17564-1] DR GeneID; 17872; -. DR KEGG; mmu:17872; -. DR UCSC; uc009gvt.3; mouse. [P17564-1] DR CTD; 23645; -. DR MGI; MGI:1927072; Ppp1r15a. DR eggNOG; ENOG502S745; Eukaryota. DR GeneTree; ENSGT00940000154404; -. DR HOGENOM; CLU_028812_0_0_1; -. DR InParanoid; P17564; -. DR OMA; VRAWVYR; -. DR PhylomeDB; P17564; -. DR TreeFam; TF105547; -. DR BioGRID-ORCS; 17872; 3 hits in 19 CRISPR screens. DR ChiTaRS; Ppp1r15a; mouse. DR PRO; PR:P17564; -. DR Proteomes; UP000000589; Chromosome 7. DR RNAct; P17564; protein. DR Bgee; ENSMUSG00000040435; Expressed in blood and 236 other tissues. DR Genevisible; P17564; MM. DR GO; GO:0005737; C:cytoplasm; ISO:MGI. DR GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI. DR GO; GO:0016020; C:membrane; ISO:MGI. DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005739; C:mitochondrion; ISO:MGI. DR GO; GO:0000164; C:protein phosphatase type 1 complex; ISO:MGI. DR GO; GO:0019901; F:protein kinase binding; ISO:MGI. DR GO; GO:0008157; F:protein phosphatase 1 binding; ISO:MGI. DR GO; GO:0019903; F:protein phosphatase binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0019888; F:protein phosphatase regulator activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IMP:MGI. DR GO; GO:1903912; P:negative regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:0032515; P:negative regulation of phosphoprotein phosphatase activity; ISO:MGI. DR GO; GO:0035308; P:negative regulation of protein dephosphorylation; ISO:MGI. DR GO; GO:1903573; P:negative regulation of response to endoplasmic reticulum stress; IDA:ParkinsonsUK-UCL. DR GO; GO:1990441; P:negative regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress; IDA:ParkinsonsUK-UCL. DR GO; GO:0070262; P:peptidyl-serine dephosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:1903917; P:positive regulation of endoplasmic reticulum stress-induced eIF2 alpha dephosphorylation; ISO:MGI. DR GO; GO:0010628; P:positive regulation of gene expression; IDA:ParkinsonsUK-UCL. DR GO; GO:1902310; P:positive regulation of peptidyl-serine dephosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:0032516; P:positive regulation of phosphoprotein phosphatase activity; ISO:MGI. DR GO; GO:0045943; P:positive regulation of transcription by RNA polymerase I; IDA:ParkinsonsUK-UCL. DR GO; GO:0070972; P:protein localization to endoplasmic reticulum; ISO:MGI. DR GO; GO:0060734; P:regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:0036496; P:regulation of translational initiation by eIF2 alpha dephosphorylation; ISO:MGI. DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:ParkinsonsUK-UCL. DR InterPro; IPR019523; Prot_Pase1_reg-su15A/B_C. DR Pfam; PF10488; PP1c_bdg; 1. PE 1: Evidence at protein level; KW Alternative splicing; Apoptosis; Endoplasmic reticulum; Membrane; KW Mitochondrion; Mitochondrion outer membrane; Phosphoprotein; KW Reference proteome; Repeat; Stress response; Translation regulation; KW Ubl conjugation. FT CHAIN 1..657 FT /note="Protein phosphatase 1 regulatory subunit 15A" FT /id="PRO_0000096665" FT TOPO_DOM 1..21 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:O75807" FT INTRAMEM 22..39 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:O75807" FT TOPO_DOM 40..657 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:O75807" FT REPEAT 283..322 FT /note="1" FT REPEAT 323..360 FT /note="2" FT REPEAT 361..398 FT /note="3" FT REPEAT 399..436 FT /note="4" FT REPEAT 437..451 FT /note="5; truncated" FT REGION 1..60 FT /note="Required for localization in the endoplasmic FT reticulum" FT /evidence="ECO:0000250|UniProtKB:O75807" FT REGION 283..451 FT /note="4.5 X approximate repeats" FT REGION 323..503 FT /note="Interaction with SMAD7" FT /evidence="ECO:0000250" FT REGION 443..548 FT /note="Interaction with KMT2A/MLL1" FT /evidence="ECO:0000250" FT REGION 529..576 FT /note="Interaction with SMARCB1" FT /evidence="ECO:0000250" FT COMPBIAS 455..458 FT /note="Poly-Glu" FT MOD_RES 239 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:O75807" FT MOD_RES 368 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:O75807" FT MOD_RES 406 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:O75807" FT MOD_RES 505 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:O75807" FT VAR_SEQ 284..360 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:16141072" FT /id="VSP_031651" FT MUTAGEN 549 FT /note="V->E: Abolishes interaction with PP1." FT /evidence="ECO:0000269|PubMed:11381086" FT CONFLICT 224 FT /note="P -> H (in Ref. 2; BAE39419)" FT /evidence="ECO:0000305" FT CONFLICT 271 FT /note="E -> G (in Ref. 2; BAE32770)" FT /evidence="ECO:0000305" FT CONFLICT 505 FT /note="Y -> C (in Ref. 2; BAE32770)" FT /evidence="ECO:0000305" SQ SEQUENCE 657 AA; 71840 MW; 9B217001019C38A7 CRC64; MAPSPRPQHV LHWRDAHNFY LLSPLMGLLS RAWSRLRGPE VPEAWLAKTV TGADQIEAAA LLTPTPVSGN LLPHGETEES GSPEQSQAAQ RLCLVEAESS PPETWGLSNV DEYNAKPGQD DLREKEMERT AGKATLQPAG LQGADKRLGE VVAREEGVAE PAYPTSQLEG GPAENEEDGE TVKTYQASAA SIAPGYKPST PVPFLGEAEH QATEEKGTEN KADPSNSPSS GSHSRAWEYY SREKPKQEGE AKVEAHRAGQ GHPCRNAEAE EGGPETTFVC TGNAFLKAWV YRPGEDTEEE DNSDSDSAEE DTAQTGATPH TSAFLKAWVY RPGEDTEEED SDSDSAEEDT AQTGATPHTS AFLKAWVYRP GEDTEEENSD LDSAEEDTAQ TGATPHTSAF LKAWVYRPGE DTEEENSDLD SAEEDTAQTG ATPHTSPFLK AWVYRPGEDT EDDTEEEEDS ENVAPGDSET ADSSQSPCLQ PQRCLPGEKT KGRGEEPPLF QVAFYLPGEK PESPWAAPKL PLRLQRRLRL FKAPTRDQDP EIPLKARKVH FAEKVTVHFL AVWAGPAQAA RRGPWEQFAR DRSRFARRIA QAEEKLGPYL TPDSRARAWA RLRNPSLPQS EPRSSSEATP LTQDVTTPSP LPSETPSPSL YLGGRRG //