PPP1R15A

Summary

PPP1R15A (protein phosphatase 1 regulatory subunit 15A, HGNC:14375) is a protein-coding gene on chromosome 19q13.2, encoding Protein phosphatase 1 regulatory subunit 15A (O75807). Recruits the serine/threonine-protein phosphatase PPP1CA to prevents excessive phosphorylation of the translation initiation factor eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis initiated by stress-inducible kinases and facilitating recovery of cells from st…. In precision oncology, PPP1R15A RS557806 confers sensitivity to FOLFIRI Regimen + Bevacizumab in Colorectal Cancer (CIViC Level B).

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.

Source: NCBI Gene 23645 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 33 total
• Druggable target: yes
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_014330

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14375
Approved symbol	PPP1R15A
Name	protein phosphatase 1 regulatory subunit 15A
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	GADD34
Ensembl gene	ENSG00000087074
Ensembl biotype	protein_coding
OMIM	611048
Entrez	23645

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000200453, ENST00000600406, ENST00000704025, ENST00000704026, ENST00000704027, ENST00000859687, ENST00000955399, ENST00000955400

RefSeq mRNA: 1 — MANE Select: NM_014330 NM_014330

CCDS: CCDS12738

Canonical transcript exons

ENST00000200453 — 3 exons

Exon	Start	End
ENSE00000389459	48873225	48874898
ENSE00001233149	48875614	48876058
ENSE00003990614	48872421	48872651

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 98.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 280.9755 / max 23737.5844, expressed in 1829 samples.

FANTOM5 promoters (33 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176829	258.9764	1829
176861	3.1481	932
176860	2.9679	864
176832	2.8961	563
176831	1.7346	851
176862	1.4679	705
176840	0.9202	333
176859	0.9173	424
176835	0.8024	245
176834	0.7503	280

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	98.90	gold quality
lower esophagus mucosa	UBERON:0035834	98.34	gold quality
omental fat pad	UBERON:0010414	97.99	gold quality
monocyte	CL:0000576	97.98	gold quality
peritoneum	UBERON:0002358	97.91	gold quality
vena cava	UBERON:0004087	97.90	gold quality
sural nerve	UBERON:0015488	97.79	gold quality
upper lobe of left lung	UBERON:0008952	97.57	gold quality
mononuclear cell	CL:0000842	97.53	gold quality
granulocyte	CL:0000094	97.43	gold quality
tibial nerve	UBERON:0001323	97.43	gold quality
skin of abdomen	UBERON:0001416	97.40	gold quality
gall bladder	UBERON:0002110	97.40	gold quality
leukocyte	CL:0000738	97.35	gold quality
ascending aorta	UBERON:0001496	97.10	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.07	gold quality
left uterine tube	UBERON:0001303	97.05	gold quality
skin of leg	UBERON:0001511	97.04	gold quality
thoracic aorta	UBERON:0001515	96.97	gold quality
upper lobe of lung	UBERON:0008948	96.88	gold quality
apex of heart	UBERON:0002098	96.85	gold quality
saphenous vein	UBERON:0007318	96.84	gold quality
right atrium auricular region	UBERON:0006631	96.83	gold quality
aorta	UBERON:0000947	96.73	gold quality
right lung	UBERON:0002167	96.67	gold quality
popliteal artery	UBERON:0002250	96.63	gold quality
tibial artery	UBERON:0007610	96.62	gold quality
left coronary artery	UBERON:0001626	96.60	gold quality
adipose tissue of abdominal region	UBERON:0007808	96.60	gold quality
coronary artery	UBERON:0001621	96.48	gold quality

Single-cell (SCXA)

Detected in 27 experiment(s), a significant marker in 23.

Experiment	Marker?	Max mean expression
E-CURD-53	yes	5589.02
E-HCAD-23	yes	4289.57
E-HCAD-31	yes	3402.99
E-MTAB-8495	yes	3164.41
E-MTAB-8142	yes	3085.69
E-GEOD-93593	yes	2469.34
E-MTAB-10885	yes	1756.83
E-MTAB-8559	yes	583.91
E-MTAB-9154	yes	555.86
E-HCAD-1	yes	52.33
E-CURD-88	yes	51.05
E-CURD-122	yes	50.27
E-CURD-112	yes	48.10
E-HCAD-4	yes	46.99
E-MTAB-6701	yes	39.39

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
CDKN1A	Activation
DDIT3	Repression
TP53	Activation

Upstream regulators (CollecTRI, top): ATF3, ATF4, ATF6, DDIT3, GATA2, JUN, NCK1, NCK2

Literature-anchored findings (GeneRIF, showing 40)

• SNF5/INI1 protein facilitates the function of the growth arrest and DNA damage-inducible protein and modulated protein phosphatase-1 activity (PMID:12016208)
• GADD 34 may play an important role in melanoma progression (PMID:12168790)
• the GADD34-mediated cellular stress response is suppressed by BAG-1 (PMID:12724406)
• Human Gadd34 lacking the viral homology domain does not interfere with normal Gadd34-induced apoptosis in cultured cells. This suggests that viral similarity sequences may be required for Gadd34-mediated functions other than apoptosis. (PMID:12813455)
• These findings suggest that phenethylisothiocyanate creates an oxidative cellular environment that induces DNA damage and GADD153, 34 and 45 gene activation, which in turn helps trigger apoptosis (PMID:14635187)
• GADD34-PP1c recruited by Smad7 inhibits TGFbeta-induced cell cycle arrest. (PMID:14718519)
• the up-regulation of GADD34 in response to global ischaemia in the human brain plus its influence on protein synthesis and DNA repair suggests that this protein may have the potential to influence cell survival (PMID:15541008)
• GADD34 may perform important functions in cardiac tissue in response to ischaemia. (PMID:16337513)
• During conditions of cell stress, GADD34 forms a stable complex with tuberous sclerosis complex (TSC) 1/2, causes TSC2 dephosphorylation, and inhibits signaling by mammalian target of the rapamycin (mTOR). (PMID:17273797)
• mechanisms that control GADD34 levels in human cells (PMID:18794359)
• GADD34 translation is regulated by a unique 5’UTR uORF mechanism to ensure proper GADD34 expression during eIF2alpha phosphorylation (PMID:19131336)
• Infectious bronchitis virus has developed a combination of two mechanisms, i.e., blocking PKR activation and inducing GADD34 expression, to maintain de novo protein synthesis in IBV-infected cells and, meanwhile, to enhance viral replication. (PMID:19776135)
• The role of the PP1/GADD34 complex in the molecular cascade is to the translocation of CRT to the outer leaflet of the plasma membrane. (PMID:19901557)
• The data suggest that EBNA3C interacts with Gadd34, activating the upstream component of the UPR-unfolded protein response (eIF2alpha phosphorylation) while preventing downstream UPR events (XBP1 activation and ATF6 cleavage). (PMID:20040105)
• the association of with ER modulates intracellular trafficking and proteasomal degradation of GADD34, and in turn, its ability to modify ER morphology (PMID:21518769)
• Low GADD34 expression is associated with malignant mesothelioma. (PMID:23412101)
• Nuclear export of HTLV-1 basic leucine-zipper factor (HBZ) is essential for its interaction with GADD34 and increased phosphorylation of S6 kinase, which is an established downstream target of the mTOR pathway. (PMID:23708656)
• GADD34 phosphorylation on tyrosine 262 modulates endoplasmic reticulum stress signaling and cell fate. (PMID:24092754)
• GADD34 may play a neuroprotective role against amyloid-beta toxicity. (PMID:25204313)
• GADD34 enhances autophagy and suppresses apoptosis stimulated by LPS combined with amino acid deprivation through regulation of mTOR signaling pathway in macrophages. (PMID:25659802)
• GADD34 promotes cell survival and adaptation to increased extracellular osmolarity by increasing the uptake of small neutral amino acids via the amino acid transporter SNAT2. (PMID:26041779)
• stress pathways lead to the induction of the protein GADD34, which appears to provide protection against the toxic effects of the secreted virulence factors in Pseudomonas aeruginosa infection (PMID:26083346)
• The data highlight independent interactions of PP1 and eIF2alpha with GADD34, demonstrating that GADD34 functions as a scaffold both in vitro and in cells (PMID:26095357)
• Data indicate that protein phosphatase 1 subunit GADD34 directly interacts with eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha). (PMID:26100893)
• GADD34 was increased in neurons of human Alzheimer’s disease (AD) brains. Additionally, this finding was also observed in oligodendrocytes in human AD brains. GADD34 could be a therapeutic target for preventing ER stress in neuronal cells in AD. (PMID:26142647)
• The reactive oxygen species-generating NADPH oxidase-4 (Nox4) is induced downstream of ATF4, binds to a PP1-targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 activity to increase eIF2alpha phosphorylation and ATF4 levels. (PMID:26742780)
• The results suggest that dephosphorylation of eIF2a by GADD34 plays an important role in doxorubicin resistance of MCF-7/ADR cells. (PMID:26743901)
• Data of this study strengthen the evidence of an unfolded protein response during the course of RA and provide an insight of the potential interest in GADD34 as a relevant marker for RA. (PMID:26829377)
• ANXA11 rs1049550 and PPP1R15A rs557806 may improve the identification of mCRC patients sensitive to bevacizumab regimens, and further validation is required in large cohorts (PMID:27177629)
• reduction of GADD34 expression significantly suppressed tumor, and resulted in decreased accumulation of MDSCs and T-cells, and inhibition of GADD34 reduced secretion of vascular epithelial growth factor alpha and transforming growth factor beta by MDSCs (PMID:27630304)
• GADD34 constitutes a mechanistic link between endoplasmic reticulum stress and mTOR inactivation, therefore promotes cell survival during endoplasmic reticulum stress. (PMID:27992581)
• The results highlighted a novel role for the GADD34/PP1alpha complex in coordinating the dephosphorylation and reactivation of eIF2alpha and SIRT1 to determine cell fate following oxidative stress. (PMID:28984870)
• Findings highlight that the phosphatase regulator, GADD34, also functions as a kinase scaffold in response to chronic oxidative stress and recruits CK1 and oxidized TDP-43 to facilitate its phosphorylation, as seen in TDP-43 proteinopathies. (PMID:29109149)
• Compared with normal controls, the wild type TT and allele T of rs611251 of PPP1R15A showed higher frequency in gastric carcinoma, nasopharyngeal carcinomas and lymphomas. (PMID:29186961)
• Inhibition of IRE1 modifies the hypoxic regulation of GADD34 family gene expression in cultured glioma cells. (PMID:29227599)
• Depletion of HES1 increased cell death in response to endoplasmic reticulum stress in mouse and human cells, in a manner that depended on the pro-apoptotic gene growth arrest and DNA damage-inducible protein GADD34. (PMID:29491143)
• Loss of GADD34 cause vanishing white matter disease due to translation defects. (PMID:29632131)
• these findings suggest that GADD34 inhibits TRAIL-induced HCC cell apoptosis through TRAF6- and ERK-mediated stabilization of MCL-1. (PMID:30782845)
• GADD34 plays an essential role in autophagy by tuning translation during starvation, thus enabling lysosomal biogenesis and a sustained autophagic flux. Hence, the TFEB-GADD34 axis integrates the mTORC1 and ISR pathways in response to starvation. (PMID:32978159)
• Higher-order phosphatase-substrate contacts terminate the integrated stress response. (PMID:34625748)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppp1r15a	ENSDARG00000069135
mus_musculus	Ppp1r15a	ENSMUSG00000040435
rattus_norvegicus	Ppp1r15a	ENSRNOG00000020938
drosophila_melanogaster	PPP1R15	FBGN0034948

Paralogs (1): PPP1R15B (ENSG00000158615)

Protein

Protein identifiers

Protein phosphatase 1 regulatory subunit 15A — O75807 (reviewed: O75807)

Alternative names: Growth arrest and DNA damage-inducible protein GADD34, Myeloid differentiation primary response protein MyD116 homolog

All UniProt accessions (4): O75807, A0A994J4D6, A0A994J786, M0QXL1

UniProt curated annotations — full annotation on UniProt →

Function. Recruits the serine/threonine-protein phosphatase PPP1CA to prevents excessive phosphorylation of the translation initiation factor eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis initiated by stress-inducible kinases and facilitating recovery of cells from stress. Down-regulates the TGF-beta signaling pathway by promoting dephosphorylation of TGFB1 by PP1. May promote apoptosis by inducing p53/TP53 phosphorylation on ‘Ser-15’. Plays an essential role in autophagy by tuning translation during starvation, thus enabling lysosomal biogenesis and a sustained autophagic flux. Also acts a viral restriction factor by attenuating HIV-1 replication. Mechanistically, mediates the inhibition of HIV-1 TAR RNA-mediated translation. (Microbial infection) Promotes enterovirus 71 replication by mediating the internal ribosome entry site (IRES) activity of viral 5’-UTR.

Subunit / interactions. Interacts with PPP1CA. Interacts with EIF2S1. Interacts with PCNA. Interacts with LYN and KMT2A/MLL1. Interacts with PPP1R1A and SMARCB1. Interacts with SMAD7. Interacts with BAG1. Interacts with NOX4. (Microbial infection) Interacts with enterovirus 71/EV71 non-structural protein precursor 3CD; this interaction promotes EV71 replication.

Subcellular location. Endoplasmic reticulum membrane. Mitochondrion outer membrane.

Post-translational modifications. Phosphorylated at multiple Ser/Thr residues. Phosphorylated on tyrosine by LYN; which impairs its antiproliferative activity. Phosphorylation at Tyr-262 enhances proteasomal degradation, this position is dephosphorylated by PTPN2. Polyubiquitinated. Exhibits a rapid proteasomal degradation with a half-life under 1 hour, ubiquitination depends on endoplasmic reticulum association.

Induction. Specifically produced in response to stress: in absence of stress, some upstream open reading frame (uORF) of this transcript is translated, thereby preventing its translation. By methyl methanesulfonate and ionizing irradiation. By IL24/interleukin-24 in melanoma cells; which induces apoptosis. By viral infection including enterovirus 71/EV71 or HIV-1.

Miscellaneous. The phosphatase activity of the PPP1R15A-PP1 complex toward EIF2S1 is specifically inhibited by Salubrinal, a drug that protects cells from endoplasmic reticulum stress.

Similarity. Belongs to the PPP1R15 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O75807-1	1	yes
O75807-2	2

RefSeq proteins (1): NP_055145* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019523	Prot_Pase1_reg-su15A/B_C	Domain
IPR051254	PPP1R15	Family

Pfam: PF10488

UniProt features (64 total): compositionally biased region 14, sequence variant 11, region of interest 8, mutagenesis site 8, modified residue 5, repeat 4, helix 4, sequence conflict 3, topological domain 2, splice variant 2, chain 1, intramembrane region 1, strand 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4XPN	X-RAY DIFFRACTION	2.29
7NXV	X-RAY DIFFRACTION	2.55
8QZZ	X-RAY DIFFRACTION	3.35
7NZM	ELECTRON MICROSCOPY	3.96

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75807-F1	49.95	0.05

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (5): 143, 262, 391, 434, 512

Mutagenesis-validated functional residues (8):

Position	Phenotype
25	localizes to cytoplasm, degraded more slowly.
29	localizes to cytoplasm.
262	significantly reduced turnover.
555–558	reduces interaction with smarcb1.
556–558	impairs pp1 activation.
612	reduces pp1-binding; when associated with k-614.
614	reduces pp1-binding; when associated with k-612.
618	reduces pp1-binding.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2173788	Downregulation of TGF-beta receptor signaling
R-HSA-9648895	Response of EIF2AK1 (HRI) to heme deficiency

MSigDB gene sets: 441 (showing top): ATF_B, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_REGULATION_OF_TRANSLATION_IN_RESPONSE_TO_STRESS, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, MATTIOLI_MGUS_VS_PCL, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, MENSE_HYPOXIA_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_TRANSLATIONAL_INITIATION, CREBP1_Q2, NAGASHIMA_NRG1_SIGNALING_UP, BILD_SRC_ONCOGENIC_SIGNATURE

GO Biological Process (14): regulation of translational initiation (GO:0006446), apoptotic process (GO:0006915), DNA damage response (GO:0006974), positive regulation of translational initiation in response to stress (GO:0032058), response to endoplasmic reticulum stress (GO:0034976), regulation of translation in response to endoplasmic reticulum stress (GO:0036490), regulation of translational initiation in response to stress (GO:0043558), regulation of cell cycle (GO:0051726), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059), protein localization to endoplasmic reticulum (GO:0070972), positive regulation of signal transduction by p53 class mediator (GO:1901798), negative regulation of PERK-mediated unfolded protein response (GO:1903898), regulation of translation (GO:0006417), regulation of protein metabolic process (GO:0051246)

GO Molecular Function (7): protein phosphatase 1 binding (GO:0008157), protein phosphatase regulator activity (GO:0019888), protein kinase binding (GO:0019901), molecular adaptor activity (GO:0060090), eukaryotic initiation factor eIF2 binding (GO:0071074), protein phosphatase activator activity (GO:0072542), protein binding (GO:0005515)

GO Cellular Component (9): protein phosphatase type 1 complex (GO:0000164), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
TGF-beta receptor signaling activates SMADs	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	5
translational initiation	3
cellular response to stress	3
cellular anatomical structure	3
intracellular membrane-bounded organelle	3
translation	2
response to endoplasmic reticulum stress	2
regulation of translation in response to stress	2
protein phosphatase binding	2
phosphoprotein phosphatase activity	2
binding	2
endomembrane system	2
regulation of translation	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
response to stress	1
positive regulation of translational initiation	1
regulation of translational initiation	1
cell cycle	1
regulation of cellular process	1
intrinsic apoptotic signaling pathway	1
protein localization to organelle	1
signal transduction by p53 class mediator	1
regulation of signal transduction by p53 class mediator	1
positive regulation of intracellular signal transduction	1
PERK-mediated unfolded protein response	1
negative regulation of endoplasmic reticulum unfolded protein response	1
regulation of PERK-mediated unfolded protein response	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
protein metabolic process	1
regulation of macromolecule metabolic process	1
regulation of primary metabolic process	1
phosphatase regulator activity	1
kinase binding	1
molecular_function	1
translation initiation factor binding	1
phosphatase activator activity	1
protein phosphatase regulator activity	1

Protein interactions and networks

STRING

3083 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPP1R15A	PPP1CC	P36873	990
PPP1R15A	PPP1CB	P37140	989
PPP1R15A	DDIT3	P35638	926
PPP1R15A	EIF2S1	P05198	923
PPP1R15A	EIF2AK3	Q9NZJ5	901
PPP1R15A	PPP1CA	P08129	895
PPP1R15A	SMAD7	O15105	856
PPP1R15A	ATF3	P18847	803
PPP1R15A	ATF6	P18850	779
PPP1R15A	ATF4	P18848	777
PPP1R15A	ERO1A	Q96HE7	726
PPP1R15A	SMARCB1	Q12824	722
PPP1R15A	EIF2AK2	P19525	697
PPP1R15A	CALR	P27797	691
PPP1R15A	DDX53	Q86TM3	691

IntAct

45 interactions, top by confidence:

A	B	Type	Score
PPP1CA	PPP1R15A	psi-mi:“MI:0407”(direct interaction)	0.820
PPP1CA	PPP1R15A	psi-mi:“MI:0915”(physical association)	0.820
PPP1CA	PPP1R15A	psi-mi:“MI:0403”(colocalization)	0.820
PPP1R15A	PPP1CA	psi-mi:“MI:0915”(physical association)	0.820
PPP1R15A	PPP1CA	psi-mi:“MI:0914”(association)	0.820
PPP1R15A	EIF2S1	psi-mi:“MI:0915”(physical association)	0.620
PPP1R15A	EIF2S1	psi-mi:“MI:0914”(association)	0.620
PPP1R15A	TARDBP	psi-mi:“MI:0915”(physical association)	0.600
TARDBP	PPP1R15A	psi-mi:“MI:0915”(physical association)	0.600
TARDBP	PPP1R15A	psi-mi:“MI:0914”(association)	0.600
PPP1R15A	POP4	psi-mi:“MI:0914”(association)	0.530
PPP1R1A	PPP1R15A	psi-mi:“MI:0915”(physical association)	0.510
PPP1R15A	PPP1R1A	psi-mi:“MI:0915”(physical association)	0.510
CTBP2	PPP1R15A	psi-mi:“MI:0915”(physical association)	0.510
Dlg4	PPP1R15A	psi-mi:“MI:0407”(direct interaction)	0.440
	PPP1R15A	psi-mi:“MI:0915”(physical association)	0.400
PPP1R15A	PLEC	psi-mi:“MI:0915”(physical association)	0.400
PPP1R15A	PPP1R15A	psi-mi:“MI:0915”(physical association)	0.400
PPP1R15A	PRKCE	psi-mi:“MI:0915”(physical association)	0.400
PPP1R15A		psi-mi:“MI:0915”(physical association)	0.370
ZNF512B	PPP1R15A	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (72): PPP1R15A (Two-hybrid), PPP1R15A (Two-hybrid), PPP1R15A (Reconstituted Complex), PPP1R15A (Affinity Capture-Western), PPZ1 (Reconstituted Complex), PLEKHA1 (Affinity Capture-MS), MINK1 (Affinity Capture-MS), BAG1 (Two-hybrid), ZNF92 (Affinity Capture-MS), POP4 (Affinity Capture-MS), MUM1 (Affinity Capture-MS), BBX (Affinity Capture-MS), PPP1R15A (Reconstituted Complex), BAG1 (Affinity Capture-Western), HSPA8 (Affinity Capture-Western)

ESM2 similar proteins: A0A0J9YX94, A0A0J9YXQ4, A0A0J9YY54, A0A494C1R9, A5D7L8, A6NDY0, A6NKD2, A7E321, E9PGG2, F6SZT2, O14771, O19110, O75807, O88852, P0CV98, P0CV99, P0CW00, P0CW01, P0CW24, P17564, P78358, Q01534, Q0P5N2, Q15735, Q2KI51, Q2M329, Q587J8, Q5DTT8, Q5R5G8, Q5R6R8, Q5SV97, Q60465, Q62881, Q69ZB3, Q6P752, Q86V59, Q8BSI6, Q8IWY8, Q8N3D4, Q8VD63

Diamond homologs: O75807, P08353, P17564, P28283, P36313, P37318, P37319, Q2KI51, Q5SWA1, Q60465, Q6IN02, Q8BFW3, Q65212, P0C753, P0C754, P0C755, P0C756

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
LYN	up-regulates	PPP1R15A	phosphorylation
PPP1R15A	up-regulates	PPP1CC	binding
PPP1R15A	up-regulates	PPP1CC	relocalization
SMAD7	up-regulates	PPP1R15A	binding
BAG1	“down-regulates activity”	PPP1R15A
ATF4	“up-regulates quantity by expression”	PPP1R15A	“transcriptional regulation”
DDIT3	“up-regulates quantity by expression”	PPP1R15A	“transcriptional regulation”
PPP1R15A	“up-regulates activity”	PPP1CC	binding
TFEB	“up-regulates quantity by expression”	PPP1R15A	“transcriptional regulation”

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

33 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

243 predictions. Top by Δscore:

Variant	Effect	Δscore
19:48872648:GCCG:G	donor_gain	1.0000
19:48872650:CG:C	donor_gain	1.0000
19:48872651:GG:G	donor_gain	1.0000
19:48872651:GGT:G	donor_loss	1.0000
19:48872652:GTG:G	donor_loss	1.0000
19:48872652:GTGA:G	donor_gain	1.0000
19:48872656:G:GG	donor_gain	1.0000
19:48872647:AGCCG:A	donor_gain	0.9900
19:48872648:GCCGG:G	donor_gain	0.9900
19:48872649:CCG:C	donor_gain	0.9900
19:48872653:T:A	donor_loss	0.9900
19:48872654:GA:G	donor_gain	0.9900
19:48872655:A:AG	donor_gain	0.9900
19:48875547:C:A	acceptor_gain	0.9900
19:48875557:ATCCG:A	acceptor_gain	0.9900
19:48873223:A:AG	acceptor_gain	0.9800
19:48873224:G:GG	acceptor_gain	0.9800
19:48874896:AAGG:A	donor_loss	0.9800
19:48874897:AGG:A	donor_loss	0.9800
19:48874899:G:GA	donor_loss	0.9800
19:48874900:T:G	donor_loss	0.9800
19:48875557:ATCC:A	acceptor_gain	0.9800
19:48875561:G:A	acceptor_gain	0.9800
19:48872649:CCGG:C	donor_gain	0.9700
19:48872650:CGG:C	donor_gain	0.9700
19:48872651:GGTG:G	donor_gain	0.9700
19:48872652:G:C	donor_gain	0.9700
19:48873224:GCCC:G	acceptor_gain	0.9700
19:48873224:GCCCA:G	acceptor_gain	0.9700
19:48875560:C:CA	acceptor_gain	0.9700

AlphaMissense

4334 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:48875722:T:C	F592L	0.991
19:48875724:C:A	F592L	0.991
19:48875724:C:G	F592L	0.991
19:48875620:T:C	F558L	0.986
19:48875622:C:A	F558L	0.986
19:48875622:C:G	F558L	0.986
19:48875694:G:C	W582C	0.985
19:48875694:G:T	W582C	0.985
19:48875723:T:C	F592S	0.984
19:48875656:T:A	W570R	0.977
19:48875656:T:C	W570R	0.977
19:48875658:G:C	W570C	0.975
19:48875658:G:T	W570C	0.975
19:48875692:T:A	W582R	0.974
19:48875692:T:C	W582R	0.974
19:48875723:T:G	F592C	0.973
19:48875732:G:C	R595P	0.972
19:48875621:T:C	F558S	0.969
19:48875711:A:T	D588V	0.966
19:48875680:C:A	R578S	0.957
19:48875731:C:A	R595S	0.956
19:48875654:T:A	V569D	0.955
19:48875708:G:C	R587P	0.952
19:48875711:A:C	D588A	0.951
19:48875710:G:C	D588H	0.949
19:48875714:G:C	R589P	0.947
19:48875705:C:A	A586D	0.945
19:48875686:G:C	G580R	0.944
19:48875735:T:C	I596T	0.944
19:48875735:T:G	I596S	0.943

dbSNP variants (sampled 300 via entrez): RS1000282316 (19:48876478 C>T), RS1000313900 (19:48873475 A>G), RS1000659805 (19:48870534 AG>A), RS1002696186 (19:48873825 G>A), RS1003013536 (19:48871599 C>A,G,T), RS1003030683 (19:48871430 C>A,T), RS1005135530 (19:48872194 T>C,G), RS1005877746 (19:48871549 C>T), RS1006297696 (19:48876361 C>G), RS1006328678 (19:48876517 T>C), RS1006403135 (19:48871168 C>T), RS1006845928 (19:48871399 C>G,T), RS1006937297 (19:48872144 A>G), RS1007243131 (19:48870693 G>C), RS1007317288 (19:48871886 G>A)

Disease associations

OMIM: gene MIM:611048 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST004611_155	High light scatter reticulocyte count	6.000000e-13
GCST004612_177	High light scatter reticulocyte percentage of red cells	1.000000e-14
GCST004619_94	Reticulocyte fraction of red cells	3.000000e-15
GCST004621_169	Red cell distribution width	5.000000e-12
GCST004622_80	Reticulocyte count	1.000000e-12
GCST006804_7	Red cell distribution width	9.000000e-12
GCST90002385_519	High light scatter reticulocyte count	2.000000e-34
GCST90002386_213	High light scatter reticulocyte percentage of red cells	6.000000e-35
GCST90002386_214	High light scatter reticulocyte percentage of red cells	5.000000e-38
GCST90002387_150	Immature fraction of reticulocytes	5.000000e-19
GCST90002390_662	Mean corpuscular hemoglobin	3.000000e-14
GCST90002392_78	Mean corpuscular volume	6.000000e-10
GCST90002404_539	Red cell distribution width	8.000000e-34
GCST90002404_540	Red cell distribution width	4.000000e-12
GCST90002405_556	Reticulocyte count	4.000000e-29
GCST90002406_534	Reticulocyte fraction of red cells	2.000000e-34

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0009188	Red cell distribution width
EFO:0004527	mean corpuscular hemoglobin

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630805 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
PPP1R15A RS557806	FOLFIRI Regimen + Bevacizumab	Colorectal Cancer	Sensitivity/Response	CIViC B	EID1325

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.01	IC50	977	nM	CHEMBL2369159

PubChem BioAssay actives

1 with measured affinity, of 1 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(E)-(2,3-dichlorophenyl)methylideneamino]guanidine	1668281: Inhibition of amino-terminal MBP-tagged/carboxy-terminal His6-tagged human PPP1R15A (325 to 626 residues)	ic50	0.9770	uM

CTD chemical–gene interactions

214 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Thapsigargin	increases reaction, affects cotreatment, increases expression, decreases reaction	9
sodium arsenite	decreases expression, decreases reaction, increases expression	7
Tobacco Smoke Pollution	increases expression	6
Tunicamycin	decreases reaction, increases expression	6
Cyclosporine	increases expression	6
Cadmium Chloride	decreases expression, increases abundance, increases expression	6
Cisplatin	increases expression, decreases response to substance, affects expression, affects cotreatment, decreases expression (+1 more)	5
Formaldehyde	increases expression	5
Cadmium	increases abundance, increases expression	4
Particulate Matter	increases expression, affects cotreatment, affects expression, increases reaction, increases abundance	4
bisphenol A	affects expression, affects cotreatment, decreases expression	3
arsenite	decreases expression, increases expression, affects reaction, increases phosphorylation, increases secretion (+3 more)	3
Arsenic Trioxide	decreases expression, increases expression	3
Air Pollutants	affects expression, increases abundance, increases expression	3
Benzo(a)pyrene	increases expression	3
Cannabidiol	increases expression, affects cotreatment	3
Copper	affects binding, decreases expression, increases expression	3
Tetrachlorodibenzodioxin	increases expression	3
cobaltous chloride	increases expression	2
didecyldimethylammonium	increases expression	2
epigallocatechin gallate	decreases reaction, increases expression, affects cotreatment	2
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases expression, decreases reaction, increases expression	2
imeglimin	affects cotreatment, increases expression, increases reaction	2
Bortezomib	increases expression	2
Rosiglitazone	increases expression	2
Zoledronic Acid	affects cotreatment, increases expression	2
Acetaminophen	increases expression	2
Amiodarone	increases expression	2
Vehicle Emissions	affects expression, increases reaction, increases expression	2
Carbamazepine	affects expression	2

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4629319	Binding	Inhibition of amino-terminal MBP-tagged/carboxy-terminal His6-tagged human PPP1R15A (325 to 626 residues)	Monovalent protein-degraders - Insights and future perspectives. — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E2HG	HAP1 PPP1R15A (-) 2	Cancer cell line	Male
CVCL_TF65	HAP1 PPP1R15A (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.