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SMG1

gene
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Also known as LIPKIAA0421ATX

Summary

SMG1 (SMG1 nonsense mediated mRNA decay associated PI3K related kinase, HGNC:30045) is a protein-coding gene on chromosome 16p12.3, encoding Serine/threonine-protein kinase SMG1 (Q96Q15). Serine/threonine protein kinase involved in both mRNA surveillance and genotoxic stress response pathways. It is a common-essential gene (DepMap: required in 99.5% of cancer cell lines).

This gene encodes a protein involved in nonsense-mediated mRNA decay (NMD) as part of the mRNA surveillance complex. The protein has kinase activity and is thought to function in NMD by phosphorylating the regulator of nonsense transcripts 1 protein. Alternatively spliced transcript variants have been described, but their full-length nature has yet to be determined.

Source: NCBI Gene 23049 — RefSeq curated summary.

At a glance

  • GWAS associations: 3
  • Clinical variants (ClinVar): 94 total
  • Druggable target: yes
  • Cancer dependency (DepMap): dependent in 99.5% of screened cell lines (common-essential)
  • MANE Select transcript: NM_015092

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:30045
Approved symbolSMG1
NameSMG1 nonsense mediated mRNA decay associated PI3K related kinase
Location16p12.3
Locus typegene with protein product
StatusApproved
AliasesLIP, KIAA0421, ATX
Ensembl geneENSG00000157106
Ensembl biotypeprotein_coding
OMIM607032
Entrez23049

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 10 protein_coding, 5 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000446231, ENST00000532700, ENST00000561940, ENST00000561947, ENST00000562668, ENST00000563235, ENST00000563448, ENST00000563836, ENST00000565224, ENST00000565324, ENST00000566328, ENST00000567737, ENST00000568038, ENST00000568239, ENST00000569122, ENST00000569764, ENST00000940395

RefSeq mRNA: 1 — MANE Select: NM_015092 NM_015092

CCDS: CCDS45430

Canonical transcript exons

ENST00000446231 — 63 exons

ExonStartEnd
ENSE000010303641881194818812127
ENSE000010303761882992618830115
ENSE000012012521881176118811867
ENSE000012012651881544018815651
ENSE000012012671881630218816529
ENSE000012012741881729118817470
ENSE000012012791881950218819654
ENSE000012012921882928618829755
ENSE000012013031883021918830369
ENSE000012013151883420418834438
ENSE000012013201883489218835164
ENSE000012013241883593318836212
ENSE000012013301883636018836532
ENSE000012013371883725318837443
ENSE000012013431883801418838232
ENSE000012013491883835718838466
ENSE000012013561883855118838689
ENSE000014182521880486018809646
ENSE000015059131883294018833166
ENSE000015059141885023718850467
ENSE000015059151885206718852205
ENSE000015059161885231818852462
ENSE000015059171885358318853867
ENSE000015059181885465618854904
ENSE000015059191885817018858290
ENSE000015059381888216518882338
ENSE000015964281889086318890921
ENSE000016085481888509018885162
ENSE000016096301886662118866775
ENSE000016226331887136418871482
ENSE000016250211887218418872345
ENSE000016253101887080118870888
ENSE000016353631887949518879719
ENSE000016382971885955618859703
ENSE000016461721882803118828168
ENSE000016518151886066718860776
ENSE000016551471887061018870711
ENSE000016602151889221818892354
ENSE000016654421887249418872624
ENSE000016877731887612418876393
ENSE000016895901885902218859181
ENSE000016911731888554118885666
ENSE000016924521886985418869994
ENSE000017007181886910418869303
ENSE000017083901888407018884167
ENSE000017137051886365018863851
ENSE000017313931886852318868719
ENSE000017498431886400218864144
ENSE000017933271888937218889585
ENSE000018032051887713118877232
ENSE000025929401892595018926408
ENSE000034961071884781618848033
ENSE000035095371884994918850126
ENSE000035288381884156518841794
ENSE000035307601884745318847607
ENSE000035577641886819018868354
ENSE000035751011884542918845651
ENSE000035971441881517518815281
ENSE000036193651883969818839946
ENSE000036605391884220818842454
ENSE000036829961884921718849378
ENSE000036963061889605218896207
ENSE000036985851889679318896956

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 98.32.

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
upper leg skinUBERON:000426298.32gold quality
sural nerveUBERON:001548898.30gold quality
colonic epitheliumUBERON:000039798.12gold quality
skin of hipUBERON:000155498.01gold quality
calcaneal tendonUBERON:000370196.68gold quality
epithelium of nasopharynxUBERON:000195196.62gold quality
parietal pleuraUBERON:000240096.32gold quality
adrenal tissueUBERON:001830395.89gold quality
mucosa of sigmoid colonUBERON:000499395.58gold quality
visceral pleuraUBERON:000240195.44gold quality
jejunal mucosaUBERON:000039995.29gold quality
biceps brachiiUBERON:000150795.19gold quality
jejunumUBERON:000211594.82gold quality
colonic mucosaUBERON:000031794.79gold quality
tonsilUBERON:000237294.75gold quality
trabecular bone tissueUBERON:000248394.64gold quality
superior surface of tongueUBERON:000737194.62gold quality
gingival epitheliumUBERON:000194994.51gold quality
endothelial cellCL:000011594.46gold quality
renal medullaUBERON:000036294.32gold quality
oral cavityUBERON:000016794.31gold quality
germinal epithelium of ovaryUBERON:000130494.29gold quality
body of tongueUBERON:001187694.08gold quality
pylorusUBERON:000116694.00gold quality
superficial temporal arteryUBERON:000161493.96gold quality
Brodmann (1909) area 23UBERON:001355493.94gold quality
skeletal muscle tissue of biceps brachiiUBERON:000450293.86gold quality
skeletal muscle tissue of rectus abdominisUBERON:000451193.84gold quality
gastrocnemiusUBERON:000138893.81gold quality
gingivaUBERON:000182893.79gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 4.

ExperimentMarker?Max mean expression
E-CURD-122yes22.24
E-GEOD-125970yes6.85
E-MTAB-6678yes6.49
E-MTAB-7381no1270.51
E-MTAB-8894no459.12
E-MTAB-6524no109.59
E-ENAD-27no3.81
E-CURD-112no2.47
E-ANND-3no0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

366 targeting SMG1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-3613-3P100.0076.367965
HSA-MIR-4481100.0066.421669
HSA-MIR-3134100.0066.43777
HSA-MIR-4533100.0069.482758
HSA-MIR-5692A100.0074.406850
HSA-MIR-8485100.0077.574731
HSA-MIR-186-5P99.9970.833707
HSA-MIR-428299.9975.366408
HSA-MIR-366299.9973.825684
HSA-MIR-548N99.9871.944170
HSA-MIR-1213699.9872.815713
HSA-MIR-19A-3P99.9875.332762
HSA-MIR-19B-3P99.9875.442754
HSA-MIR-539-3P99.9870.741616
HSA-MIR-433-3P99.9869.371203
HSA-MIR-485-3P99.9870.681585
HSA-MIR-4745-5P99.9865.951028
HSA-MIR-569699.9872.364487
HSA-MIR-477599.9875.006394
HSA-MIR-806899.9873.852376
HSA-MIR-520D-5P99.9873.344883
HSA-MIR-524-5P99.9873.434882
HSA-MIR-548P99.9872.253784
HSA-MIR-4482-3P99.9872.503147
HSA-MIR-3617-3P99.9867.86918
HSA-MIR-314899.9775.066478
HSA-MIR-3065-5P99.9771.563281
HSA-MIR-493-5P99.9672.472382
HSA-MIR-4666A-3P99.9671.713434
HSA-MIR-570-3P99.9672.414910

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 39)

  • Expression of hSMG-1 is required for optimal p53 activation after cellular exposure to genotoxic stress, and depletion of hSMG-1 leads to spontaneous DNA damage and increased sensitivity to ionizing radiation. (PMID:15175154)
  • hSMG-1 teams with ATM and ATR to insure the overall quality of the transcriptome in human cells [review] (PMID:15279777)
  • Thus, the SMG-1-mediated phosphorylation of Upf1 occurs on the association of SURF with EJC, which provides the link between the EJC and recognition of PTCs and triggers NMD (PMID:16452507)
  • distantly located N- and C-terminal sequences are essential for the intrinsic kinase activity of SMG-1 (PMID:17229728)
  • hSMG-1 plays an important role in cell survival during TNFalpha-induced stress (PMID:18326048)
  • hSMG-1 and ATM sequentially and independently regulate the G1 checkpoint during oxidative stress (PMID:18332866)
  • SMG-1 negatively regulated HIF-1alpha activity in hypoxia, in part through blocking MAPK activation. (PMID:19406746)
  • SMG-8 and SMG-9 suppress SMG-1 kinase activity in the isolated SMG-1 complex and are involved in Nonsense-mediated mRNA decay in both mammals and nematodes (PMID:19417104)
  • The phosphatidylinositol 3-kinase pathway plays a critical role in the transfer of signal from morphine stimuli to mu opioid receptor gene transcription. (PMID:19765550)
  • The results of this study indicated a significant impact of brief naturalistic stressors on AS-mediated regulation of gene expression in peripheral leukocytes, and suggest the SMG-1 splice variant as a potential biomarker for acute psychological stress (PMID:20723581)
  • The CK2 phospho-dependent interaction between TEL2 and the R2TP complex affects phosphatidylinositol 3-kinase-related kinase functions and is essential for mTOR and SMG1 stability in vivo. (PMID:20864032)
  • large-scale conformational changes induced by SMG-8 after SMG-9-mediated recruitment tune SMG-1 kinase activity to modulate nonsense-mediated mRNA decay (PMID:21245168)
  • Hyperglycemia (both 10 and 20 mM)-treated monocyte showed up-regulated phosphorylation of p101 and p110gamma subunits of PI-3 kinase in comparison to 5 mM glucose. (PMID:21307779)
  • The inhibition of hSMG-1 significantly enhances the sensitivity of human lung cancer H1299 cells to gemcitabine and cisplatin. (PMID:21418860)
  • SMG1 plays independent roles in responding to DNA, RNA damage and a broader role in protection against cellular stress tna other member of the PIKK family. (PMID:21701263)
  • stress granule formation appears more complex than originally envisaged and hSMG-1 plays a central role in this process. (PMID:21911475)
  • Levels of SMG-1 expression negatively correlated with HPV status in cancer cell lines and tumors. (PMID:22247495)
  • the inflammation observed in Smg1 haploinsufficiency contributes to susceptibility to cancer, and Smg1-deficient animals represent a model of inflammation-enhanced cancer development (PMID:23277562)
  • Data indicate that down-regulation of SMG1 expression is mediated by miRNA-125 binding to a microRNA response element in the 3’ untranslated region of SMG1 mRNA, which leads to degradation of the SMG1 mRNA. (PMID:23583196)
  • Novel role for SMG-1 is identified in regulating Cdc25A and suppressing oncogenic CDK2 driven proliferation, confirming SMG-1 as a tumor suppressor. (PMID:24107632)
  • This study demonstrated the quantitative regulation of Upf1 and Upf2 proteins by ubiquitin-proteasome system and SMG1. (PMID:24173962)
  • Downregulation of SMG1 causes the reduction in the level of Upf1 phosphorylation and delays adipogenesis, suggesting the functional involvement of SMG1 in adipogenesis via SMD. (PMID:24185201)
  • SMG1 protein levels were significantly reduced in brain. (PMID:24204929)
  • We conclude that SMG-1 is downregulated in HCC and may represent a promising biomarker for predicting the prognosis of HCC, including the prognosis of early-stage patients. (PMID:24700316)
  • SMG1 regulates NMD by recruiting UPF1 and UPF2 to distinct nearby positions, and can form a complex with UPF2 in vivo in an UPF1-independent manner. (PMID:25002321)
  • A genome-wide RNA interference screen Hepatocellular carcinoma cell lines revealed the role of suppressor of SMG-1 as determinant of sorafenib resistance. (PMID:25017961)
  • SMG1 was hypermethylated in 66% of AML samples compared with none in controls. mTOR expression level was negatively correlated to SMG1 expression in AML patients which indicated that SMG1 and mTOR maybe act antagonistically to regulate AML cell growth. (PMID:25257528)
  • Knock down of the expression of SMG-1 inhibited tumor cell proliferation and induced the chemosensitivity of pancreatic cancer cells in vitro. (PMID:25760059)
  • ionizing radiation (IR) inhibits the activity of SMG1, a phosphoinositide-3-kinase-like kinase family member, reducing the binding of SMG1 to a specific region near exon 9 of p53 precursor mRNA and promoting the binding of ribosomal protein L26 (RPL26) to p53 pre-mRNA (PMID:28288992)
  • Because SMG-1-p53 signaling attenuates production of mitochondrial ROS. (PMID:28749708)
  • SMG-1 is a target of the oncomiRs, miR-192 and -215, and that its downregulation is associated with tumor size and serosal invasion of gastric cancer (GC). SMG-1 appears to mediate at least some of the oncogenic function of miR-192 and -215 by participating in epithelial-mesenchymal transition, triggered by activation of the Wnt pathway in GC. (PMID:29239144)
  • SMG1 variants c.4249A>G and c.103G>A are associated with pancreatic cancer in large study (PMID:31469826)
  • MicroRNA-18a promotes cancer progression through SMG1 suppression and mTOR pathway activation in nasopharyngeal carcinoma. (PMID:31659158)
  • Cryo-EM structure of SMG1-SMG8-SMG9 complex. (PMID:31729466)
  • This study reports the 3.45-A resolution cryo-EM structure of human SMG1-SMG8-SMG9, a phosphatidylinositol-3-kinase (PI(3)K)-related protein kinase (PIKK) complex central to messenger RNA surveillance. (PMID:31792449)
  • Structure of substrate-bound SMG1-8-9 kinase complex reveals molecular basis for phosphorylation specificity. (PMID:32469312)
  • SMG1 and CDK12 Link DeltaNp63alpha Phosphorylation to RNA Surveillance in Keratinocytes. (PMID:34761935)
  • Large-scale genomic sequencing reveals adaptive opportunity of targeting mutated-PI3Kalpha in early and advanced HER2-positive breast cancer. (PMID:34842356)
  • SMG1, a nonsense-mediated mRNA decay (NMD) regulator, as a candidate therapeutic target in multiple myeloma. (PMID:36400430)

Cross-species orthologs

5 orthologs

OrganismSymbolGene ID
danio_reriosmg1ENSDARG00000054570
mus_musculusSmg1ENSMUSG00000030655
rattus_norvegicusSmg1ENSRNOG00000047386
drosophila_melanogasternonCFBGN0263968
caenorhabditis_eleganssmg-1WBGENE00004879

Paralogs (5): ATM (ENSG00000149311), ATR (ENSG00000175054), TRRAP (ENSG00000196367), MTOR (ENSG00000198793), PRKDC (ENSG00000253729)

Protein

Protein identifiers

Serine/threonine-protein kinase SMG1 — Q96Q15 (reviewed: Q96Q15)

Alternative names: Lambda/iota protein kinase C-interacting protein, Nonsense mediated mRNA decay-associated PI3K-related kinase SMG1

All UniProt accessions (10): Q96Q15, A0A087X1K8, E9PNP6, H3BPS6, H3BQN7, H3BR09, I3L0W2, I3L144, I3L400, J3KRA9

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine protein kinase involved in both mRNA surveillance and genotoxic stress response pathways. Recognizes the substrate consensus sequence [ST]-Q. Plays a central role in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons by phosphorylating UPF1/RENT1. Recruited by release factors to stalled ribosomes together with SMG8 and SMG9 (forming the SMG1C protein kinase complex), and UPF1 to form the transient SURF (SMG1-UPF1-eRF1-eRF3) complex. In EJC-dependent NMD, the SURF complex associates with the exon junction complex (EJC) through UPF2 and allows the formation of an UPF1-UPF2-UPF3 surveillance complex which is believed to activate NMD. Also acts as a genotoxic stress-activated protein kinase that displays some functional overlap with ATM. Can phosphorylate p53/TP53 and is required for optimal p53/TP53 activation after cellular exposure to genotoxic stress. Its depletion leads to spontaneous DNA damage and increased sensitivity to ionizing radiation (IR). May activate PRKCI but not PRKCZ.

Subunit / interactions. Component of the SMG1C complex composed of SMG1, SMG8 and SMG9; the recruitment of SMG8 to SMG1 N-terminus induces a large conformational change in the SMG1 C-terminal head domain containing the catalytic domain. Component of the transient SURF (SMG1-UPF1-eRF1-eRF3) complex. Part of a complex composed of SMG1, DHX34 and UPF1; within the complex DHX34 acts as a scaffolding protein to facilitate SMG1 phosphorylation of UPF1. Interacts with PRKCI. Interacts with TELO2 and TTI1. Interacts with RUVBL1 and RUVBL2. Interacts with UPF2. Interacts with DHX34 (via C-terminus); the interaction is RNA-independent.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Widely expressed, with highest level in heart and skeletal muscle. Expressed in placenta, brain, lung and spleen, but not in liver.

Post-translational modifications. Autophosphorylated.

Activity regulation. Inhibited by caffeine, LY294002 and wortmannin.

Miscellaneous. This gene is located in a region of chromosome 16 that contains 2 segmental duplications. Other genes that are highly related to this exist, but they probably represent pseudogenes.

Similarity. Belongs to the PI3/PI4-kinase family.

Isoforms (4)

UniProt IDNamesCanonical?
Q96Q15-11yes
Q96Q15-22
Q96Q15-33
Q96Q15-44, BLIP

RefSeq proteins (1): NP_055907* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR000403PI3/4_kinase_cat_domDomain
IPR003152FATC_domDomain
IPR011009Kinase-like_dom_sfHomologous_superfamily
IPR011989ARM-likeHomologous_superfamily
IPR014009PIK_FATDomain
IPR016024ARM-type_foldHomologous_superfamily
IPR018936PI3/4_kinase_CSConserved_site
IPR031559SMG1Family
IPR035175SMG1_NDomain
IPR036940PI3/4_kinase_cat_sfHomologous_superfamily
IPR039414SMG1_PIKKcDomain
IPR050517DDR_Repair_KinaseFamily

Pfam: PF00454, PF02260, PF15785, PF17229

Enzyme classification (BRENDA):

  • EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

SubstrateKm (mM)Measurements
ATP0.0007–0.6411
KKRAARATSNVFA0.013–0.0453
PAH1 PHOSPHATIDATE PHOSPHATASE0.00022
RRRLSSLRA0.0036–0.00372
GTP0.461
KKRAARASSNVFA0.021
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA0.00931
MYELIN BASIC PROTEIN0.1451

Catalyzed reactions (Rhea), 2 shown:

  • L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
  • L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (259 total): helix 133, strand 35, sequence variant 35, turn 17, region of interest 9, sequence conflict 9, compositionally biased region 6, modified residue 6, domain 3, splice variant 3, chain 1, repeat 1, mutagenesis site 1

Structure

Experimental structures (PDB)

10 structures.

PDBMethodResolution (Å)
7PW8ELECTRON MICROSCOPY2.82
6Z3RELECTRON MICROSCOPY2.97
7PW6ELECTRON MICROSCOPY3.05
7PW9ELECTRON MICROSCOPY3.12
7PW4ELECTRON MICROSCOPY3.27
7PW5ELECTRON MICROSCOPY3.4
6L54ELECTRON MICROSCOPY3.43
6SYTELECTRON MICROSCOPY3.45
7PW7ELECTRON MICROSCOPY3.59
6L53ELECTRON MICROSCOPY3.63

Predicted structure (AlphaFold)

No AlphaFold model available for Q96Q15 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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 (6): 173, 3550, 3556, 3570, 3573, 3577

Mutagenesis-validated functional residues (1):

PositionPhenotype
2335loss of function.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

IDPathway
R-HSA-975957Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)
R-HSA-8953854Metabolism of RNA
R-HSA-927802Nonsense-Mediated Decay (NMD)

MSigDB gene sets: 325 (showing top): GOBP_CHROMOSOME_ORGANIZATION, E2F_Q4_01, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, PAX4_01, MORF_MSH3, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, MORF_BRCA1, GOBP_PEPTIDYL_SERINE_MODIFICATION, MORF_ATRX, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, AREB6_01, GOBP_TELOMERE_ORGANIZATION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, BROWNE_HCMV_INFECTION_16HR_UP

GO Biological Process (9): nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:0000184), DNA repair (GO:0006281), mRNA export from nucleus (GO:0006406), DNA damage response (GO:0006974), peptidyl-serine phosphorylation (GO:0018105), regulation of telomere maintenance (GO:0032204), protein autophosphorylation (GO:0046777), phosphatidylinositol phosphate biosynthetic process (GO:0046854), phosphorylation (GO:0016310)

GO Molecular Function (12): RNA binding (GO:0003723), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), diacylglycerol-dependent serine/threonine kinase activity (GO:0004697), ATP binding (GO:0005524), telomeric repeat DNA binding (GO:0042162), metal ion binding (GO:0046872), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), chromatoid body (GO:0033391)

Reactome top-level categories

Rollup of top-2 pathways:

CategoryPathways
Nonsense-Mediated Decay (NMD)1
Metabolism of RNA1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
cellular anatomical structure3
protein phosphorylation2
protein kinase activity2
nuclear-transcribed mRNA catabolic process1
DNA metabolic process1
DNA damage response1
RNA export from nucleus1
gene expression1
mRNA transport1
cellular response to stress1
peptidyl-serine modification1
telomere maintenance1
regulation of chromosome organization1
regulation of DNA metabolic process1
glycerophospholipid biosynthetic process1
phosphate-containing compound metabolic process1
nucleic acid binding1
kinase activity1
phosphotransferase activity, alcohol group as acceptor1
catalytic activity, acting on a protein1
protein serine/threonine kinase activity1
adenyl ribonucleotide binding1
purine ribonucleoside triphosphate binding1
sequence-specific DNA binding1
cation binding1
nucleoside phosphate binding1
heterocyclic compound binding1
binding1
transferase activity, transferring phosphorus-containing groups1
catalytic activity1
intracellular membrane-bounded organelle1
nuclear lumen1
intracellular anatomical structure1
cytoplasm1
cytoplasmic ribonucleoprotein granule1

Protein interactions and networks

STRING

3386 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
SMG1SMG9Q9H0W8999
SMG1UPF2Q9HAU5999
SMG1SMG8Q8ND04999
SMG1UPF1Q92900999
SMG1UPF3AQ9H1J1998
SMG1SMG5Q9UPR3962
SMG1GSPT1P15170938
SMG1ETF1P46055932
SMG1SMG7Q92540928
SMG1SMG6Q86US8921
SMG1UPF3BQ9BZI7906
SMG1DHX34Q14147845
SMG1HBS1LQ9Y450832
SMG1TRRAPQ9Y4A5814
SMG1NOMO3P69849762

IntAct

73 interactions, top by confidence:

ABTypeScore
RBM8AEIF4A3psi-mi:“MI:0914”(association)0.950
SMG1UPF2psi-mi:“MI:0407”(direct interaction)0.800
SMG1UPF1psi-mi:“MI:0914”(association)0.760
RBM8ASMG1psi-mi:“MI:0914”(association)0.760
SMG9SMG8psi-mi:“MI:0914”(association)0.710
SMG1EIF4A3psi-mi:“MI:0914”(association)0.690
SMG1SMG8psi-mi:“MI:0914”(association)0.690
SMG1MAGOHpsi-mi:“MI:0914”(association)0.640
GYPATCAF2psi-mi:“MI:0914”(association)0.640
PDGFRBPIK3R2psi-mi:“MI:0914”(association)0.610
TELO2MTORpsi-mi:“MI:0914”(association)0.600
SMG1TTI1psi-mi:“MI:0914”(association)0.600
RUVBL1TTI1psi-mi:“MI:0914”(association)0.600
TTI1POLR2Epsi-mi:“MI:0914”(association)0.600
EPHA1EXOC5psi-mi:“MI:0914”(association)0.530
RBM8APABPC1psi-mi:“MI:0914”(association)0.530
RBM8ARPS16psi-mi:“MI:0914”(association)0.530
NECAP2AP2A2psi-mi:“MI:0914”(association)0.530
ANKRD22ESYT2psi-mi:“MI:0914”(association)0.530

BioGRID (167): SMG1 (Affinity Capture-Western), SMG1 (Affinity Capture-MS), SMG1 (Affinity Capture-MS), SMG1 (Affinity Capture-MS), SMG1 (Affinity Capture-MS), SMG1 (Affinity Capture-MS), SMG1 (Affinity Capture-RNA), SMG1 (Proximity Label-MS), SMG1 (Affinity Capture-MS), SMG1 (Affinity Capture-MS), SMG1 (Affinity Capture-MS), SMG1 (Affinity Capture-MS), SMG1 (Proximity Label-MS), SMG1 (Proximity Label-MS), SMG1 (Two-hybrid)

ESM2 similar proteins: A0JM49, A2AKG8, B0V0U5, B1AUR6, C5J7W8, E1BGH8, E1C231, E1C2Z0, E7FGT5, E7FH61, E9Q3L2, F6S215, O08662, O60287, O94822, P42356, P57678, P78527, P97313, Q13315, Q13535, Q14146, Q1RLU1, Q2TAW0, Q3TQQ9, Q3URQ0, Q571H0, Q5RDK1, Q5VW36, Q5WNI9, Q5XI94, Q5ZM41, Q62388, Q6A009, Q6DFV1, Q6PQD5, Q6ZRQ5, Q7SY48, Q86XI2, Q8BKX6

Diamond homologs: A2YH41, C5J7W8, O01510, O74630, P0CP60, P0CP61, Q13535, Q2U639, Q4IB89, Q4WVM7, Q5ABX0, Q5BHE2, Q5Z987, Q61CW2, Q6BV76, Q6CAD2, Q6CP76, Q6FRZ9, Q6FX42, Q7RZT9, Q8BKX6, Q95Q95, Q96Q15, Q9DE14, Q9FKS4, Q9JKK8, P38110, P38111, P54676, Q02099, Q13315, Q54ER4, Q59LR2, Q5EAK6, Q62388, Q6P435, Q6PQD5, Q751J3, Q75DB8, Q86C65

SIGNOR signaling

4 interactions.

AEffectBMechanism
SMG1up-regulatesTP53phosphorylation
SMG1up-regulatesUPF1phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 72 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

PathwayPartnersFoldFDR
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)1120.3×2e-09
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)511.1×5e-03
Regulation of expression of SLITs and ROBOs810.4×2e-04

GO biological processes:

GO termPartnersFoldFDR
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay1074.3×3e-14
mRNA export from nucleus628.2×2e-05
mRNA splicing, via spliceosome68.7×5e-03
protein stabilization77.4×3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance25
Likely benign8
Benign4

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

24011 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
16:18809575:C:AW3660C1.000
16:18809575:C:GW3660C1.000
16:18809577:A:GW3660R1.000
16:18809577:A:TW3660R1.000
16:18809584:C:AW3657C1.000
16:18809584:C:GW3657C1.000
16:18809586:A:GW3657R1.000
16:18809586:A:TW3657R1.000
16:18809588:C:TG3656D1.000
16:18809589:C:GG3656R1.000
16:18809597:A:GL3653P1.000
16:18809625:C:GA3644P1.000
16:18811805:C:GG3622R1.000
16:18811810:A:GL3620S1.000
16:18811812:C:AK3619N1.000
16:18811812:C:GK3619N1.000
16:18811832:A:GW3613R1.000
16:18811832:A:TW3613R1.000
16:18811843:G:TA3609E1.000
16:18811851:G:CN3606K1.000
16:18811851:G:TN3606K1.000
16:18819596:G:TA3267D1.000
16:18819607:C:AW3263C1.000
16:18819607:C:GW3263C1.000
16:18819608:C:GW3263S1.000
16:18819609:A:GW3263R1.000
16:18819609:A:TW3263R1.000
16:18819614:A:GL3261P1.000
16:18819614:A:TL3261H1.000
16:18819617:C:GR3260P1.000

dbSNP variants (sampled 300 via entrez): RS1000005264 (16:18863134 G>A), RS1000005594 (16:18874587 T>G), RS1000084356 (16:18815003 C>A,G), RS1000110096 (16:18829203 C>A), RS1000167204 (16:18812983 T>G), RS1000176388 (16:18805333 T>C), RS1000209014 (16:18903152 T>C), RS1000260326 (16:18894235 G>C), RS1000281397 (16:18808660 C>G), RS1000339118 (16:18926680 C>A,G,T), RS1000366520 (16:18813200 G>A), RS1000429518 (16:18857746 G>A), RS1000438192 (16:18868987 T>C,G), RS1000454612 (16:18818394 CA>C,CAA), RS1000503698 (16:18814274 T>C)

Disease associations

OMIM: gene MIM:607032 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

StudyTraitp-value
GCST006979_250Heel bone mineral density1.000000e-09
GCST008513_30Health literacy7.000000e-06
GCST010002_110Refractive error9.000000e-10

EFO canonical traits (2, from GWAS)

EFO IDTrait name
EFO:0009270heel bone mineral density
EFO:0010104health literacy measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1795195 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — SMG1 subfamily

Most potent curated ligand interactions (1 total), top 1:

LigandActionAffinityParameter
compound 11j [PMID: 23021994]Inhibition9.96pIC50

ChEMBL bioactivities

24 potent at pChembl≥5 of 24 total, top 24 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
10.00IC500.1nMCHEMBL2158859
9.96IC500.11nMCHEMBL2158866
9.70IC500.2nMCHEMBL2158863
9.70IC500.2nMCHEMBL2158011
8.52IC503nMCHEMBL2158857
8.52IC503nMCHEMBL2158853
8.22IC506nMCHEMBL2158855
7.96IC5011nMCHEMBL2158845
7.66IC5022nMCHEMBL2158843
7.60IC5025nMCHEMBL2158854
7.10IC5080nMCHEMBL2158851
6.96IC50110nMCHEMBL300389
6.93Kd116.9nMCHEMBL5653589
6.93ED50116.9nMCHEMBL5653589
6.60IC50250nMCHEMBL2158849
6.55IC50280nMCHEMBL2158844
6.51IC50310nMCHEMBL2158856
6.48IC50330nMCHEMBL2158848
6.43IC50370nMCHEMBL2158847
6.35IC50450nMCHEMBL2158842
6.00IC501000nMCHEMBL2158846
5.96IC501100nMCHEMBL2158850
5.90IC501250nMCHEMBL601661
5.82IC501500nMCHEMBL2158852

PubChem BioAssay actives

29 with measured affinity, of 76 total; 29 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
1-methyl-3-[4-[4-[2-(3-sulfamoylanilino)pyrimidin-4-yl]-2-pyridinyl]phenyl]urea695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0001uM
1-methyl-3-[4-[4-[2-(4-methyl-3-sulfamoylanilino)pyrimidin-4-yl]-2-pyridinyl]phenyl]urea695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0001uM
1-methyl-3-[4-[4-[2-[4-methyl-3-(methylsulfamoyl)anilino]pyrimidin-4-yl]-2-pyridinyl]phenyl]urea695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0001uM
1-methyl-3-[4-[4-[2-[3-(methylsulfamoyl)anilino]pyrimidin-4-yl]-2-pyridinyl]phenyl]urea695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0001uM
1-[4-[4-[2-[3-(dimethylsulfamoyl)-4-methylanilino]pyrimidin-4-yl]-2-pyridinyl]phenyl]-3-methylurea695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0001uM
1-[4-[4-[2-[4-chloro-3-(diethylsulfamoyl)anilino]pyrimidin-4-yl]-2-pyridinyl]phenyl]-3-methylurea695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0001uM
1-[4-[4-[2-[4-chloro-3-(methylsulfamoyl)anilino]pyrimidin-4-yl]-2-pyridinyl]phenyl]-3-methylurea695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0001uM
1-[4-[4-[2-[4-chloro-3-(dimethylsulfamoyl)anilino]pyrimidin-4-yl]-2-pyridinyl]phenyl]-3-methylurea695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0001uM
1-[4-[4-[2-[3-(diethylsulfamoyl)-4-methylanilino]pyrimidin-4-yl]-2-pyridinyl]phenyl]-3-methylurea695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0002uM
1-[4-[4-[2-[3-(diethylsulfamoyl)anilino]pyrimidin-4-yl]-2-pyridinyl]phenyl]-3-methylurea695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0002uM
3-[[4-(2-piperidin-1-yl-4-pyridinyl)pyrimidin-2-yl]amino]benzenesulfonamide695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0030uM
3-[[4-[2-(diethylamino)-4-pyridinyl]pyrimidin-2-yl]amino]benzenesulfonamide695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0030uM
3-[[4-[2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-pyridinyl]pyrimidin-2-yl]amino]benzenesulfonamide695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0060uM
3-[[4-(2-morpholin-4-yl-4-pyridinyl)pyrimidin-2-yl]amino]benzenesulfonamide695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0110uM
3-[[4-[2-(3-hydroxypropylamino)-4-pyridinyl]pyrimidin-2-yl]amino]benzenesulfonamide695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0220uM
3-[[4-[2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-pyridinyl]pyrimidin-2-yl]amino]benzenesulfonamide695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0250uM
3-[[4-(2-morpholin-4-yl-4-pyridinyl)pyrimidin-2-yl]amino]benzonitrile695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.0800uM
3-[[4-[2-(3-chloroanilino)pyrimidin-4-yl]-2-pyridinyl]amino]propan-1-ol695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.1100uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide2149448: Binding affinity to human SMG1 incubated for 45 mins by Kinobead based pull down assaykd0.1169uM
4-(2-morpholin-4-yl-4-pyridinyl)-N-[3-(trifluoromethyl)phenyl]pyrimidin-2-amine695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.2500uM
N-(3-chlorophenyl)-4-(2-morpholin-4-yl-4-pyridinyl)pyrimidin-2-amine695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.2800uM
3-[[4-[2-(4-methylpiperazin-1-yl)-4-pyridinyl]pyrimidin-2-yl]amino]benzenesulfonamide695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.3100uM
N-(3-methylphenyl)-4-(2-morpholin-4-yl-4-pyridinyl)pyrimidin-2-amine695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.3300uM
4-[[4-(2-morpholin-4-yl-4-pyridinyl)pyrimidin-2-yl]amino]benzenesulfonamide695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.3700uM
4-[[4-[3-(piperidine-1-carbonyl)phenyl]pyrimidin-2-yl]amino]benzenesulfonamide695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic500.4500uM
N-(4-chlorophenyl)-4-(2-morpholin-4-yl-4-pyridinyl)pyrimidin-2-amine695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic501.0000uM
N-(3-methoxyphenyl)-4-(2-morpholin-4-yl-4-pyridinyl)pyrimidin-2-amine695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic501.1000uM
1-[4-[1-(1,4-dioxaspiro[4.5]decan-8-yl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[5,4-d]pyrimidin-6-yl]phenyl]-3-methylurea2174221: Inhibition of human SMG1 using glutathione S-transferase-p53 as substrate by DELFIAic501.2500uM
4-(2-morpholin-4-yl-4-pyridinyl)-N-phenylpyrimidin-2-amine695753: Inhibition of human recombinant SMG1 expressed in HEK293 cells using GST-tagged p53 as substrate after 1 hr by DELFIA assayic501.5000uM

CTD chemical–gene interactions

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

ChemicalActions (top 5)PubMed papers
sodium arsenitedecreases expression, increases expression3
Benzo(a)pyreneaffects methylation, decreases expression2
Cisplatindecreases expression, decreases reaction, increases activity, decreases response to substance2
Estradioldecreases expression, increases expression2
Cyclosporinedecreases expression, increases expression2
Cadmium Chlorideincreases abundance, increases expression2
Genisteindecreases expression, increases expression2
FR900359increases phosphorylation1
bisphenol Faffects cotreatment, decreases expression1
testosterone enanthateaffects expression1
methylmercuric chlorideincreases expression1
triphenyl phosphateaffects expression1
pirinixic acidaffects binding, increases activity, increases expression1
bisphenol Adecreases expression, affects cotreatment1
nobiletindecreases reaction, increases expression1
sodium arsenatedecreases reaction, increases expression1
trichostatin Aaffects expression1
beta-lapachoneincreases expression1
arsenitedecreases reaction, affects binding1
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanoneincreases expression1
cobaltous chlorideincreases expression1
coumarinincreases phosphorylation1
perfluorooctane sulfonic aciddecreases expression1
CPG-oligonucleotideincreases expression1
bisphenol Saffects cotreatment, decreases expression1
Acetaminophenincreases expression1
Gemcitabinedecreases response to substance, decreases reaction, increases activity1
Cadmiumincreases abundance, increases expression1
Caffeineaffects phosphorylation1
Dexamethasoneaffects cotreatment, decreases expression1

ChEMBL screening assays

46 unique, capped per target: 46 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL1837981BindingInhibition of human SMG1 in HL60 cells lysate at 10 uM using post probe-labeling by LC-MS/MS analysis relative to controlSynthesis and structure-activity relationship of 4-quinolone-3-carboxylic acid based inhibitors of glycogen synthase kinase-3β. — Bioorg Med Chem Lett

Cellosaurus cell lines

5 cell lines: 5 induced pluripotent stem cell

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

CellosaurusNameCategorySex
CVCL_RK73SU042-1Induced pluripotent stem cellFemale
CVCL_RK74SU042-2Induced pluripotent stem cellFemale
CVCL_RK75SU042-3Induced pluripotent stem cellFemale
CVCL_RK76SU042-4Induced pluripotent stem cellFemale
CVCL_RK77SU042-5Induced pluripotent stem cellFemale

Clinical trials (associated diseases)

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

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
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BioBTree
v2.0.2

Sources 79

This page pulls from 79 datasets indexed by BioBTree:

alphafoldalphamissenseantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticsccdscellosauruschembl_activitychembl_assaychembl_documentchembl_moleculechembl_targetciviccivic_evidenceclingen_dosageclingen_gene_validityclinical_trialsclinvarcollectrictd_gene_interactiondbsnpdepmapdiamond_similarityefoensemblentrezesm2_similarityexonfantom5_genefantom5_promotergenccgenerifgogoparentgtopdbgtopdb_interactiongwasgwas_studyhgnchpointactinterprointogenjasparmeshmimmirdbmondomsigdborphanetorthologparalogpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assaypubmedreactomereactomeparentrefseqrhearnacentralscxa_expressionscxa_gene_experimentsignorspliceaistring_interactiontranscriptufeatureuniprot