PPP1R15A

Protein phosphatase 1, regulatory subunit 15A
Identifiers
Symbols	PPP1R15A ; GADD34
External IDs	OMIM: 611048 MGI: 1100516 HomoloGene: 8639 GeneCards: PPP1R15A Gene
Gene ontology Molecular function • protein binding • protein phosphatase 1 binding • protein phosphatase type 1 regulator activity • protein kinase binding • protein phosphatase type 1 activator activity Cellular component • protein phosphatase type 1 complex • cytoplasm • mitochondrion • mitochondrial outer membrane • endoplasmic reticulum • endoplasmic reticulum membrane • Golgi apparatus • cytosol • membrane Biological process • apoptotic process • cellular response to DNA damage stimulus • cell cycle arrest • transforming growth factor beta receptor signaling pathway • positive regulation of gene expression • negative regulation of transforming growth factor beta receptor signaling pathway • endoplasmic reticulum unfolded protein response • positive regulation of translational initiation in response to stress • negative regulation of phosphoprotein phosphatase activity • positive regulation of phosphoprotein phosphatase activity • positive regulation of peptidyl-serine phosphorylation • response to endoplasmic reticulum stress • negative regulation of protein dephosphorylation • regulation of translational initiation by eIF2 alpha dephosphorylation • positive regulation of transcription from RNA polymerase I promoter • regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress • peptidyl-serine dephosphorylation • protein localization to endoplasmic reticulum • positive regulation of peptidyl-serine dephosphorylation • negative regulation of PERK-mediated unfolded protein response • negative regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation • positive regulation of endoplasmic reticulum stress-induced eIF2 alpha dephosphorylation • negative regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	23645	17872
Ensembl	ENSG00000087074	ENSMUSG00000040435
UniProt	O75807	P17564
RefSeq (mRNA)	NM_014330	NM_008654
RefSeq (protein)	NP_055145	NP_032680
Location (UCSC)	Chr 19: 48.87 – 48.88 Mb	Chr 7: 45.52 – 45.53 Mb
PubMed search

Protein phosphatase 1 regulatory subunit 15A also known as growth arrest and DNA damage-inducible protein GADD34 is a protein that in humans is encoded by the PPP1R15A gene.^[1][2][3]

The Gadd34/MyD116 gene was originally discovered as a member in a set of gadd and MyD mammalian genes encoding acidic proteins that synergistically suppress cell growth.^[4] Later on it has been characterized as a gene playing a role in ER stress-induced cell death, being a target of ATF4 that plays a role in ER-mediated cell death via promoting protein dephosphorylation of eIF2α and reversing translational inhibition.^[5]

Function

This gene is a member of a group of genes whose transcript levels are increased following stressful growth arrest conditions and treatment with DNA-damaging agents. The induction of this gene by ionizing radiation occurs in certain cell lines regardless of p53 status, and its protein response is correlated with apoptosis following ionizing radiation.^[3]

Interactions

PPP1R15A has been shown to interact with:

• BAG1^[6]
• LYN,^[7]
• MLL,^[8]
• PPP1CA,^[9][10][6]
• PPP1CB,^[9][10]
• PPP1CC,^[9][10]
• SMARCB1,^[9][8] and
• TSN.^[11]

References

1. Hollander MC, Zhan Q, Bae I, Fornace AJ Jr (Jul 1997). "Mammalian GADD34, an apoptosis- and DNA damage-inducible gene". J Biol Chem 272 (21): 13731–7. doi:10.1074/jbc.272.21.13731. PMID 9153226.
2. Korabiowska M, Betke H, Kellner S, Stachura J, Schauer A (Jan 1998). "Differential expression of growth arrest, DNA damage genes and tumour suppressor gene p53 in naevi and malignant melanomas". Anticancer Res 17 (5A): 3697–700. PMID 9413226.
3. "Entrez Gene: PPP1R15A protein phosphatase 1, regulatory (inhibitor) subunit 15A".
4. Zhan Q, Lord KA, Alamo I, Hollander MC, Carrier F, Ron D, Kohn KW, Hoffman B, Liebermann DA, Fornace AJ (April 1994). "The gadd and MyD genes define a novel set of mammalian genes encoding acidic proteins that synergistically suppress cell growth". Mol. Cell. Biol. 14 (4): 2361–71. doi:10.1128/mcb.14.4.2361. PMC: 358603. PMID 8139541.
5. Sano R, Reed JC (July 2013). "ER stress-induced cell death mechanisms". Biochim. Biophys. Acta 1833 (12): 3460–70. doi:10.1016/j.bbamcr.2013.06.028. PMID 23850759.
6. Hung WJ, Roberson RS, Taft J, Wu DY (2003). "Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions". Mol. Cell. Biol. 23 (10): 3477–86. doi:10.1128/MCB.23.10.3477-3486.2003. PMC: 164759. PMID 12724406.
7. Grishin AV, Azhipa O, Semenov I, Corey SJ (2001). "Interaction between growth arrest-DNA damage protein 34 and Src kinase Lyn negatively regulates genotoxic apoptosis". Proc. Natl. Acad. Sci. U.S.A. 98 (18): 10172–7. doi:10.1073/pnas.191130798. PMC: 56934. PMID 11517336.
8. Adler HT, Chinery R, Wu DY, Kussick SJ, Payne JM, Fornace AJ, Tkachuk DC (1999). "Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins". Mol. Cell. Biol. 19 (10): 7050–60. PMC: 84700. PMID 10490642.
9. Wu DY, Tkachuck DC, Roberson RS, Schubach WH (2002). "The human SNF5/INI1 protein facilitates the function of the growth arrest and DNA damage-inducible protein (GADD34) and modulates GADD34-bound protein phosphatase-1 activity". J. Biol. Chem. 277 (31): 27706–15. doi:10.1074/jbc.M200955200. PMID 12016208.
10. Connor JH, Weiser DC, Li S, Hallenbeck JM, Shenolikar S (2001). "Growth arrest and DNA damage-inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inhibitor 1". Mol. Cell. Biol. 21 (20): 6841–50. doi:10.1128/MCB.21.20.6841-6850.2001. PMC: 99861. PMID 11564868.
11. Hasegawa T, Isobe K (1999). "Evidence for the interaction between Translin and GADD34 in mammalian cells". Biochim. Biophys. Acta 1428 (2-3): 161–8. doi:10.1016/s0304-4165(99)00060-4. PMID 10434033.

Further reading

• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.". Gene 138 (1-2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library.". Gene 200 (1-2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Hasegawa T, Isobe K (1999). "Evidence for the interaction between Translin and GADD34 in mammalian cells.". Biochim. Biophys. Acta 1428 (2-3): 161–8. doi:10.1016/s0304-4165(99)00060-4. PMID 10434033.
• Adler HT, Chinery R, Wu DY, et al. (2000). "Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins.". Mol. Cell. Biol. 19 (10): 7050–60. PMC: 84700. PMID 10490642.
• Hasegawa T, Yagi A, Isobe K (2000). "Interaction between GADD34 and kinesin superfamily, KIF3A.". Biochem. Biophys. Res. Commun. 267 (2): 593–6. doi:10.1006/bbrc.1999.1991. PMID 10631107.
• Hasegawa T, Xiao H, Hamajima F, Isobe K (2001). "Interaction between DNA-damage protein GADD34 and a new member of the Hsp40 family of heat shock proteins that is induced by a DNA-damaging reagent.". Biochem. J. 352 (3): 795–800. doi:10.1042/0264-6021:3520795. PMC: 1221519. PMID 11104688.
• Grishin AV, Azhipa O, Semenov I, Corey SJ (2001). "Interaction between growth arrest-DNA damage protein 34 and Src kinase Lyn negatively regulates genotoxic apoptosis.". Proc. Natl. Acad. Sci. U.S.A. 98 (18): 10172–7. doi:10.1073/pnas.191130798. PMC: 56934. PMID 11517336.
• Connor JH, Weiser DC, Li S, et al. (2001). "Growth arrest and DNA damage-inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inhibitor 1.". Mol. Cell. Biol. 21 (20): 6841–50. doi:10.1128/MCB.21.20.6841-6850.2001. PMC: 99861. PMID 11564868.
• Wu DY, Tkachuck DC, Roberson RS, Schubach WH (2002). "The human SNF5/INI1 protein facilitates the function of the growth arrest and DNA damage-inducible protein (GADD34) and modulates GADD34-bound protein phosphatase-1 activity.". J. Biol. Chem. 277 (31): 27706–15. doi:10.1074/jbc.M200955200. PMID 12016208.
• Korabiowska M, Cordon-Cardo C, Betke H; et al. (2003). "GADD153 is an independent prognostic factor in melanoma: immunohistochemical and molecular genetic analysis.". Histol. Histopathol. 17 (3): 805–11. PMID 12168790.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC: 139241. PMID 12477932.
• Brush MH, Weiser DC, Shenolikar S (2003). "Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2.". Mol. Cell. Biol. 23 (4): 1292–303. doi:10.1128/MCB.23.4.1292-1303.2003. PMC: 141149. PMID 12556489.
• Hung WJ, Roberson RS, Taft J, Wu DY (2003). "Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions.". Mol. Cell. Biol. 23 (10): 3477–86. doi:10.1128/MCB.23.10.3477-3486.2003. PMC: 164759. PMID 12724406.
• Hollander MC, Poola-Kella S, Fornace AJ (2003). "Gadd34 functional domains involved in growth suppression and apoptosis.". Oncogene 22 (25): 3827–32. doi:10.1038/sj.onc.1206567. PMID 12813455.
• Powolny A, Takahashi K, Hopkins RG, Loo G (2004). "Induction of GADD gene expression by phenethylisothiocyanate in human colon adenocarcinoma cells.". J. Cell. Biochem. 90 (6): 1128–39. doi:10.1002/jcb.10733. PMID 14635187.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs.". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Shi W, Sun C, He B, et al. (2004). "GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor.". J. Cell Biol. 164 (2): 291–300. doi:10.1083/jcb.200307151. PMC: 2172339. PMID 14718519.
• Colland F, Jacq X, Trouplin V, et al. (2004). "Functional proteomics mapping of a human signaling pathway.". Genome Res. 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC: 442148. PMID 15231748.