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Schema Name MST1 Schema for Crohn's disease
Accession MS020500019.2
Gene(s) MST1, MST1R, RON
Schema Caption How a GWAS marker on MST1MST1 gene is related to increased risk of Crohn's disease
Schema Description Welcome Trust Case Control Consortium (WTCCC) identified a GWAS marker for Crohn's disease at chromosome 3, in 3p21 which spans 20 genes, an unusually high number. The primary marker SNP ( rs9858542 ) in this Crohn's disease locus lies in an intron of the BSN (bassoon, presynaptic cytomatrix protein) gene. That gene is involved in neural development and expressed in the brain, so unlikely to be relevant to Crohn's disease. Of the 20 genes spanned in this locus, the most probable candidate appears to be MST1 (Macrophage Stimulating protein), on the grounds that it is involved in the innate immune response through alteration of macrophage activity. In later GWAS studies (pmid: 23128233), rs3197999 in MST1 gene is found to be significant GWAS marker. We used this SNP to address how both increase in inflammation and delayed wound healing / leaky gut are contributing towards the increase in disease risk.
Author(s) Lipika R. Pal, Kunal Kundu, Lindley Darden and John Moult
Curator(s) John Moult
Last Modified Fri Aug 10 2018 15:13:18 GMT-0400 (Eastern Daylight Time)
Sub-state Perturbation (SSP) Annotations
Component ID: SSP1
Stage: DNA
SSP Class: Other
Other SSP Class: SNV [HET/HOM]
Modifier: NA
Ontology:
SSP Instance: rs3197999 in MST1
Confidence Score: 5
Comment: Of the 20 genes spanned in this locus, the most probable candidate appears to be MST1 (macrophage stimulating protein), on the grounds that it is involved in the innate immune response through stimulation of macrophage activity. In later GWAS, rs3197999 became established GWAS marker for Crohn's disease (Jostins et al 140 loci Crohn's disease paper). 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. After this SSP, there are conflicting data and theories at the protein level mechanism. Hence there is branching in the next mechanism components from this SSP. We are not sure which branch is correct - so AND/OR labeling in the branches.
For Evidence: PMID:23128233
Against Evidence:
Component ID: SSP2A
Stage: Protein
SSP Class: Other
Other SSP Class: Missense Variant
Modifier: NA
Ontology:
SSP Instance: R703C in MSP
Confidence Score: 5
Comment: The transcript of this protein is NP_066278. The substitution is arginine by a cysteine at the position 703 of MSP. Computational analysis methods classify it as high impact on protein function, but with no predicted impact in protein structure stability.
For Evidence: PMID:16412461, PMID:16169011
Against Evidence:
Component ID: SSP2B
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Altered
Ontology: PLOSTHES
SSP Instance: Less MSP
Confidence Score: 5
Comment: This report (pubmed id: 24409221) found no change in the RON/MST1 association constant in the presence of this SNV, but did found a lower level of protein in the serum.
For Evidence:
Against Evidence:
Component ID: SSP3
Stage: Complex
SSP Class: Protein-Protein Complex Abundance
Other SSP Class:
Modifier: Decreased
Ontology:
SSP Instance: MSP-RON complex
Confidence Score: 5
Comment: Lower fraction of RON cell surface receptor with bound MSP.
For Evidence: PMID:25193665, PMID:22087277
Against Evidence:
Component ID: SSP4A
Stage: Cell
SSP Class: Other
Other SSP Class: Cell Activation
Modifier: Altered
Ontology:
SSP Instance: Macrophage cell
Confidence Score: 3
Comment: Resident intestinal macrophages scavenge cell debris and harmless microorganisms without any induction of inflammatory responses. Mutant MSP enhances macrophage activity, which in turn increases inflammatory responses.
For Evidence: PMID:12472665, PMID:20545605, PMID:22237417
Against Evidence:
Component ID: SSP4B
Stage: Cell
SSP Class: Other
Other SSP Class: Cell Activation
Modifier: Decreased
Ontology:
SSP Instance: Epithelial cell
Confidence Score: 3
Comment: Decreased RON signaling affects epithelial cell survival and growth.
For Evidence: PMID:10688668, PMID:24084775
Against Evidence:
Component ID: SSP5A
Stage: Tissue
SSP Class: Other
Other SSP Class: Inflammation
Modifier: Increased
Ontology:
SSP Instance: Pro-inflammatory factors
Confidence Score: 5
Comment: With stimulated macrophages, production of pro-inflammatory factors, like cytokines are increased, increasing inflammatory responses. This activates innate immunity, which in turn activates adaptive immunity.
For Evidence: PMID:12472665, PMID:20545605, PMID:
Against Evidence:
Component ID: SSP5B
Stage: Tissue
SSP Class: Other
Other SSP Class: Barrier Integrity
Modifier: Decreased
Ontology:
SSP Instance: Leaky gut
Confidence Score: 5
Comment: A lower rate of wound healing will result into a leaky gut.
For Evidence: PMID:24084775, PMID:9764835
Against Evidence:
Component ID: SSP6
Stage: Phenotype
SSP Class: Other
Other SSP Class: Disease Risk
Modifier: Increased
Ontology:
SSP Instance: Crohn's disease
Confidence Score: 5
Comment: Two branches will rejoin here - both bacterial penerance and neutrophil dysfunction will lead to increased risk of Crohn's disease.
For Evidence: PMID:24913378
Against Evidence:
Biomarker(s) Annotations
Mechanism Module (MM) Annotations
Component ID: MM1A
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 those steps are telescoped/merged into this one mechansim module.
For Evidence:
Against Evidence:
Component ID: MM2A
Mechanism Class Name: Protein-Protein Interaction
Other Mechanism Class Name:
Modifer: NA
Ontology: NCIT
Mechanism Instance:
Confidence Score: 3
Comment: MST1 is activated by proteolytic cleavage under conditions of infection, and the activated form binds to the RON cell surface receptor, a tyrosine receptor kinase. R703C has been shown to lie close to the MST1/RON interface and surface plasmon resonance (SPR) measurements show an ~5 fold lower association constant between the two proteins in the presence of the missense SNV. Another report found no change in the RON/MST1 association constant in the presence of this SNV, but did found a lower level of protein in serum. Because of the contradictory evidences, confidence level is lowered to medium confidence.
For Evidence: PMID:25193665, PMID:22087277
Against Evidence: PMID:24409221
Component ID: MM2B
Mechanism Class Name:
Other Mechanism Class Name: Le Chatelier
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Lower MSP abundance leads to lower concentration of the complex with RON. Standard Le Chatelier principle - if the concentration of one member of a binary complex changes, the concentration of the complex will also change.
For Evidence:
Against Evidence:
Component ID: MM3
Mechanism Class Name: Cell Signaling
Other Mechanism Class Name:
Modifer: Decreased
Ontology: GO
Mechanism Instance: Decreased Cell signaling
Confidence Score: 5
Comment: Impaired MSP signaling. RON signaling, leading to cell activation, is reduced. After this, there is again branching, because activation of two different cell types may be relevant. We are not sure which branch is correct - so AND/OR labeling in the branches.
For Evidence: PMID:12919677
Against Evidence:
Component ID: MM4B
Mechanism Class Name:
Other Mechanism Class Name: wound healing
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Lower epithelial cell activation will lead to slowing down th e process of wound healing.
For Evidence: PMID:24084775, PMID:9764835
Against Evidence:
Component ID: MM5A
Mechanism Class Name:
Other Mechanism Class Name: Neutrophil activity
Modifer: Altered
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment: During acute inflammation in patients with IBD, the function of macrophages is compromised, characterized by reduced production of TNF-u03b1, leading to decreased numbers of neutrophils recruited to the sites of inflammation and chronic intestinal inflammation mediated by T cells. Functional neutrophils are critical to maintain intestinal homeostasis. Neutrophils can play dual role - both functional deficiency and hyperreactivity of neutrophils can cause intestinal inflammation. We are not sure here what role is operating here - so medium confidence color for this mechansim module.
For Evidence: PMID:18161747, PMID:27999328 , PMID:28857501
Against Evidence:
Component ID: MM5B
Mechanism Class Name:
Other Mechanism Class Name: Bacterial translocation
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Through a leaky gut, more bacteria can invade in, resulting into the higher concentration of bacteria in the tissue beneath the gut wall.
For Evidence: PMID:18161747
Against Evidence:
Unknown Mechanism Module (MM) Annotations
Component ID: MM1B
Comment: Another report (pubmed id: 24409221) found no change in the RON/MST1 association constant in the presence of this SNV, but did found a lower level of protein in serum. The mechansim by which this comes about is unknown - might be degradation of messenger RNA, slower translation, or shorter protein half life.
For Evidence:
Against Evidence:
Component ID: MM4A
Comment: How altered macrophage activation is leading to increase in inflammatory response is not known - so unknown mechanism module is used here.
For Evidence:
Against Evidence:
Environmental Factor Annotations
Therapeutic Interventions Annotations
Component ID: TT1
Annotation Text: TherapeuticIntervention
Comment: Whatever the down or up-stream mechanisms, lower RON signaling is very likely as lower levels of the RON/MST1 complex are involved. So a mechanism for boosting that to 'normal' levels would provide a therapeutic option. This could be done by designing a drug that bound across the interface of RON and MST1, so as to effectively increase the binding constant. May be a good target for a protein therapeutic, since this interaction takes place in the plasma.
For Evidence:
Against Evidence: