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Schema Image
Schema Name Mongersen drug effectiveness schema for Crohn's disease
Accession MS020500026.4
Gene(s) SMAD7, SMAD3, SMAD2, SMAD4, TGF-β, TGF-βR-I, TGF-βR-II TLR4, ITGAV, ITGB8
Schema Caption Relationship between Crohn's risk genetic variants and Mongersen (drug) effectiveness
Schema Description This schema is addressing regulation of the TGF-β signaling via blocking of SMAD7 transcription for Crohn's patients. Under normal conditions, TGF-β gets activated in the dendritic cell by integrin αVβ8 in response to TLR4 agonist bacterial LPS (pmid: 27782111). Binding of TGF-β to TGF-β receptor type II promotes activation of TGF-β receptor type I thus leading to SMAD2/3 phosphorylation. Phosphorylated SMAD2/3 bind to SMAD4 and this complex translocates into the nucleus where it inhibits transcription of inflammatory genes. TGF-β also induces the expression of SMAD7 - it is an immediate early response gene for TGF-β and acts in a negative feedback loop to regulate the intensity or duration of the TGF-β signal. Experimentally it is observed that (pmid: 9712726) expression of SMAD7 reaches a maximal level after 30-90 min of TGF-β signal and its expression returns to basal level after 4-6 hours. In Crohn's patients, SMAD7 is overproduced in the inflamed gut. This SMAD7, in turn, suppresses the activity of TGF-β, by interacting with TGF-β receptor type I and thus preventing SMAD2/3 phosphorylation. As a consequence of defective TGF-β signaling, immune cells produce elevated levels of inflammatory molecules, increasing Crohn's disease risk. The purpose of the drug Mongersen (developed by G. Monteleone team) (pmid: 25785968) is to suppress the activity of SMAD7 so that TGF-β can function normally and control gut inflammation. This drug uses an antisense strategy to inhibit the transcription of SMAD7 gene. There is no established evidence on how genetic variants in SMAD7, integrin αVβ8, and TLR4 from Crohn's disease patients are responding to this drug effect. We are addressing the possible relationship between these genetic variants and Mongersen drug effectiveness in this schema.
Author(s) Lipika R. Pal, Kunal Kundu, Lindley Darden and John Moult
Curator(s) Lipika R. Pal, John Moult
Last Modified Thu Feb 21 2019 16:09:34 GMT-0500 (Eastern Standard Time)
Sub-state Perturbation (SSP) Annotations
Component ID: SSP10
Stage: DNA
SSP Class: Other
Other SSP Class: SNV [HET/HOM]
Modifier: NA
Ontology:
SSP Instance: rs7240004 near SMAD7
Confidence Score: 5
Comment: GWAS marker (rs7240004, chr18: 46395022) is in the intergenic region between CTIF and SMAD7. Study groups are prioritizing SMAD7 as the potential candidate gene. As these are GWAS marker information, where relationship with increasing disease risk is based on allele frequency, so SNV can be in either heterozygous (HET) or homozygous (HOM) mode.
For Evidence: PMID:23128233 , PMID:26192919
Against Evidence:
Component ID: SSP6
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class: Complex abundance
Modifier: Decreased
Ontology: PLOSTHES
SSP Instance: Activated TGF-β
Confidence Score: 5
Comment: Decreased abundance of activated TGF-β will lead to less protein-protein interaction with TGF-β receptor II and then with TGF-β receptor I
For Evidence: PMID:24313777
Against Evidence:
Component ID: SSP12
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Increased
Ontology: PLOSTHES
SSP Instance: SMAD7
Confidence Score: 5
Comment: High level of SMAD7 for Crohn's patients.
For Evidence: PMID:23155305
Against Evidence:
Component ID: SSP1
Stage: DNA
SSP Class: Other
Other SSP Class: SNV [HET/HOM]
Modifier: NA
Ontology:
SSP Instance: rs4986790 in TLR4
Confidence Score: 5
Comment: One of the GWAS marker for Crohn's disease is at chr9:120475302 (hg19) on TLR4 gene. As these are GWAS marker information, where relationship with increasing disease risk is based on allele frequency, so SNV can be in either heterozygous (HET) or homozygous (HOM) mode.
For Evidence: PMID:28067908
Against Evidence:
Component ID: SSP2
Stage: Protein
SSP Class: Other
Other SSP Class: Missense Variant
Modifier: NA
Ontology:
SSP Instance: D259G in TLR4
Confidence Score: 5
Comment: There are 3 transcripts with multiple substitutions for this protein. The more common substitution is Asp to Gly. Other substitution is Asp to Val (less frequent). Residue number is 259 for NP_003257, 299 for NP_612564, and 99 for NP_612567.
For Evidence:
Against Evidence:
Component ID: SSP5
Stage: Protein
SSP Class: Other
Other SSP Class: Expression
Modifier: Decreased
Ontology:
SSP Instance: Lack of αVβ8 upregulation in response to LPS
Confidence Score: 3
Comment: Integrin αVβ8 expression by dendritic cells is increased by the presence of the TLR4 agonist LPS, which enhances activation of TGF-β in dendritic cells.
For Evidence: PMID:27481847, PMID:27782111, PMID:20519498
Against Evidence:
Component ID: SSP4
Stage: DNA
SSP Class: Other
Other SSP Class: SNV [HET/HOM]
Modifier: NA
Ontology:
SSP Instance: rs149169037 in ITGB8
Confidence Score: 5
Comment: One of the GWAS marker for Crohn's disease is at chr7:20577298 (hg19) on ITGB8 gene. As these are GWAS marker information, where relationship with increasing disease risk is based on allele frequency, so SNV can be in either heterozygous (HET) or homozygous (HOM) mode.
For Evidence: PMID:28067908
Against Evidence:
Component ID: SSP15
Stage: Complex
SSP Class: Protein-Protein Complex Abundance
Other SSP Class:
Modifier: Decreased
Ontology:
SSP Instance: TGF-β- TGF-βRII- TGF-βRI complex
Confidence Score: 5
Comment: Decreased abundance of activated TGF-β will lead to less protein-protein interaction with TGF-β receptor II and then with TGF-β receptor I. Excess SMAD7 will also interact with TGF-βR-I complex and inhibit the phosphorylation of TGF-βR-I.
For Evidence: PMID:24313777
Against Evidence:
Component ID: SSP16
Stage: Protein
SSP Class: Phosphorylated Protein Abundance
Other SSP Class:
Modifier: Decreased
Ontology:
SSP Instance: SMAD2, SMAD3
Confidence Score: 5
Comment: Interaction of SMAD7 with TGF-β receptor I complexes will inhibit the phosphorylation of SMAD2/3.
For Evidence: PMID:24313777, PMID:23155305
Against Evidence:
Component ID: SSP17
Stage: Complex
SSP Class: Protein-Protein Complex Abundance
Other SSP Class:
Modifier: Decreased
Ontology:
SSP Instance: SMAD2/3-SMAD4
Confidence Score: 5
Comment: Decreased phosphorylation of SMAD2/3 will inhibit the interaction with SMAD4. As there is no complex formation, it cannot move to the nucleus.
For Evidence: PMID:24313777
Against Evidence:
Component ID: SSP18
Stage: Cell
SSP Class: Other
Other SSP Class: Cell product abundance
Modifier: Increased
Ontology:
SSP Instance: Pro-inflammatory Chemokines, Cytokines
Confidence Score: 5
Comment: Activation of NF-kB pathway leads to higher expression of pro-inflammatory chemokines and cytokines.
For Evidence: PMID:24313777
Against Evidence:
Component ID: SSP19
Stage: Phenotype
SSP Class: Other
Other SSP Class: Disease risk
Modifier: Increased
Ontology:
SSP Instance: Crohn's disease
Confidence Score: 5
Comment: Increased risk of Crohn’s disease due to increase in inflmmation.
For Evidence: PMID:24313777
Against Evidence:
Component ID: SSP11
Stage: Protein
SSP Class: Post-Translational Modified Protein Abundance
Other SSP Class:
Modifier: Increased
Ontology:
SSP Instance: Acetylated SMAD7
Confidence Score: 5
Comment: Acetylated SMAD7 level is always high for Crohn's patients.
For Evidence: PMID:23155305
Against Evidence:
Component ID: SSP3
Stage: DNA
SSP Class: Other
Other SSP Class: SNV [HET/HOM]
Modifier: NA
Ontology:
SSP Instance: rs144344067 in ITGAV
Confidence Score: 5
Comment: One of the GWAS marker for Crohn's disease is at chr2:187576378 (hg19) on ITGAV gene. As these are GWAS marker information, where relationship with increasing disease risk is based on allele frequency, so SNV can be in either heterozygous (HET) or homozygous (HOM) mode.
For Evidence: PMID:28067908
Against Evidence:
Component ID: SSP7
Stage: Phenotype
SSP Class: Other
Other SSP Class: DIsease
Modifier: NA
Ontology:
SSP Instance: Crohn's disease
Confidence Score: 5
Comment: For Crohn's patients, always p300 level is very high.
For Evidence:
Against Evidence:
Component ID: SSP8
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Increased
Ontology: PLOSTHES
SSP Instance: P300
Confidence Score: 3
Comment: p300 level is increased for Crohn's patients.
For Evidence: PMID:12408818, PMID:16285943, PMID:15831498
Against Evidence:
Component ID: SSP9
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Decreased
Ontology: PLOSTHES
SSP Instance: SIRT1
Confidence Score: 3
Comment: Deacetylation protein SIRT1 is decreased for Crohn's patients.
For Evidence: PMID:12408818, PMID:16285943, PMID:15831498
Against Evidence:
Component ID: SSP13
Stage: Complex
SSP Class: Protein-Protein Complex Abundance
Other SSP Class:
Modifier: Increased
Ontology:
SSP Instance: SMAD7-SMURF
Confidence Score: 5
Comment: Excess SMAD7 interacts with SMURF1/2 to turn on the signaling for degradation of TGF-β receptor complexes.
For Evidence: PMID:14718519, PMID:16285943
Against Evidence:
Component ID: SSP14
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Decreased
Ontology: PLOSTHES
SSP Instance: TGF-β receptors
Confidence Score: 5
Comment: Decreased abundance of TGF-β receptor-I will affect the formation the complex with TGF-β and TGF-β receptor II.
For Evidence:
Against Evidence:
Biomarker(s) Annotations
Mechanism Module (MM) Annotations
Component ID: MM1
Mechanism Class Name: Protein synthesis
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance: Protein synthesis
Confidence Score: 5
Comment: Transcription and translation are believed to be normal for this SNV, and so these steps telescoped / merged into this one mechanism module of protein synthesis.
For Evidence:
Against Evidence:
Component ID: MM5
Mechanism Class Name: activation of latent TGF-β
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance: Decreased activation of latent TGF-β
Confidence Score: 5
Comment: Lack of integrin upregulation will decrease the activation of TGF-β from its latent form.
For Evidence: PMID:27481847, PMID:27782111, PMID:24313777
Against Evidence:
Component ID: MM6
Mechanism Class Name: Le Chatelier
Other Mechanism Class Name:
Modifer: NA
Ontology: NCIT
Mechanism Instance:
Confidence Score: 5
Comment: TGF-beta is interacting with TGF-betaR-II and TGF-betaR-I
For Evidence:
Against Evidence:
Component ID: MM15
Mechanism Class Name: Phosphorylation of TGF-βRI
Other Mechanism Class Name:
Modifer: Altered
Ontology:
Mechanism Instance: Decreased Phosphorylation of TGF-βRI
Confidence Score: 5
Comment: Decreased phosphorylation of TGF-β receptor I complex.
For Evidence: PMID:24313777
Against Evidence:
Component ID: MM12
Mechanism Class Name: Le Chatelier
Other Mechanism Class Name:
Modifer: NA
Ontology: NCIT
Mechanism Instance:
Confidence Score: 5
Comment: SMAD7 stably associates with TGF-beta receptor complexes
For Evidence:
Against Evidence:
Component ID: MM16
Mechanism Class Name: Protein-Protein Interaction
Other Mechanism Class Name:
Modifer: Decreased
Ontology: NCIT
Mechanism Instance:
Confidence Score: 5
Comment: Lack of phosphorylated SMAD2/3 leads to no protein-protein interaction with SMAD4.
For Evidence: PMID:24313777
Against Evidence:
Component ID: MM17
Mechanism Class Name: Activation of NF-kB pathway
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance: Activation of NF-kB pathway
Confidence Score: 5
Comment: NF-kB pathway will be activated at the nucleus.
For Evidence: PMID:24313777
Against Evidence:
Component ID: MM18
Mechanism Class Name:
Other Mechanism Class Name: Inflammation
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: More inflammation due to higher expression of pro-inflammatory Cytokines and Chemokines.
For Evidence: PMID:24313777
Against Evidence:
Component ID: MM9
Mechanism Class Name:
Other Mechanism Class Name: Acetylation of SMAD7
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: For Crohn's patient SMAD7 acetylation rate is very high.
For Evidence: PMID:23155305
Against Evidence:
Component ID: MM13
Mechanism Class Name: Protein Degradation Rate
Other Mechanism Class Name:
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: SMAD7 interacts with E3 ubiquitin ligase SMURF1/2 and marked degradation for TGF-β receptor I complexes.
For Evidence: PMID:14718519, PMID:16285943
Against Evidence:
Component ID: MM11
Mechanism Class Name:
Other Mechanism Class Name: Ubiquitination of SMAD7
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: When acetylation of SMAD7 is high, ubiquitination rate is low, as these 2 processes are competing for the same lysine residues.
For Evidence: PMID:16285943, PMID:12408818, PMID:15831498
Against Evidence:
Component ID: MM3
Mechanism Class Name: Regulation by p38 pathway
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance: Regulation by P38 pathway
Confidence Score: 3
Comment: The integrin β8 gene promoter region is known to contain binding sites for the LPS activated transcription factors p38 and AP-1, a mechanism by which LPS can specifically enhance integrin αVβ8 expression in dendritic cell.
For Evidence: PMID:20519498, PMID:27782111
Against Evidence:
Unknown Mechanism Module (MM) Annotations
Component ID: MM4
Comment: We are not sure how integrin variants in ITGAV and ITGB8 are affecting the expression. We used black box here.
For Evidence:
Against Evidence:
Component ID: MM7
Comment: We are not sure why for Crohn's disease patients there is an increased abundance of p300 and decreased abundance of SIRT1.
For Evidence:
Against Evidence:
Component ID: MM10
Comment: We are not sure how the GWAS marker is related to SMAD7 for Crohn's patients, where hihj level of acetylated SMAD7 is found.
For Evidence:
Against Evidence:
Component ID: MM2
Comment: We are uncertain about how TLR4 is contributing towards activation of the integrin. One study shows that TLR4 signaling is not required for activation of p38 MAPK pathway, however, TLR4 is required at the cell surface. We use black box here.
For Evidence: PMID:18701460
Against Evidence:
Environmental Factor Annotations
Component ID: EF1
Annotation Text: Bacterial LPS
Comment: TLR4 recognizes bacterial LPS.
For Evidence:
Against Evidence:
Therapeutic Interventions Annotations
Component ID: TT1
Annotation Text: Mongersen
Comment: This drug aims to tie up the RNA it makes using antisense strategy, thus inhibiting the production of SMAD7.
For Evidence: PMID:25785968
Against Evidence: