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Schema Name MUC1 Crohn's disease locus
Accession MS020500028.2
Gene(s) MUC1
Schema Caption The role of MUC1 genetic variant for Crohn’s disease.
Schema Description MUC1 is a membrane-bound mucin, expressed on the apical surface of the epithelial cells. This schema is addressing the effect of a GWAS marker variant rs1142287, located on SCAMP3 gene (pmid: 21102463). According to GTEX portal data, this SNV is an eQTL with target gene as MUC1, and the minor allele is over-expressed than the major one. This data is further supported by the fact that over-expressed MUC1 is related to inflammatory bowel disease (pmid: 20084048). In this schema, we are addressing how the change in expression of MUC1 is affecting barrier integrity and inflammation signal and thus contributing to Crohn's disease risk.
Author(s) Lipika R. Pal, Kunal Kundu, Lindley Darden and John Moult
Curator(s) Lipika R. Pal
Last Modified Fri Aug 10 2018 15:14:33 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: rs1142287 in MUC1
Confidence Score: 5
Comment: MUC1 mechanism schema starts with a GWAS marker variant rs1142287, a synonymous variant (NP_005689:p.Gly126Gly or, NP_443069.p.Gly100Gly), located on SCAMP3 gene at chromosome 1 (hg19: chr1:155230131).
For Evidence: PMID:21102463
Against Evidence:
Component ID: SSP2
Stage: RNA
SSP Class: mRNA Abundance
Other SSP Class:
Modifier: Increased
Ontology:
SSP Instance: MUC1 mRNA
Confidence Score: 3
Comment: Over-expression of MUC1 gene is due to the presence of GWAS marker rs1142287.
For Evidence:
Against Evidence: PMID:20084048
Component ID: SSP3
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Increased
Ontology: PLOSTHES
SSP Instance: MUC1
Confidence Score: 5
Comment: Due to overexpressed MUC1 eQTL, MUC1 protein abundance is increased.
For Evidence:
Against Evidence:
Component ID: SSP4
Stage: Protein
SSP Class: Post-Translational Modified Protein Abundance
Other SSP Class: Glycosylated protein abundance
Modifier: Decreased
Ontology:
SSP Instance: Hypoglycosylated MUC1
Confidence Score: 5
Comment: MUC1 is over-expressed in an abnormal, hypo-glycosylated form on the colonic epithelium in human Inflammatory Bowel Disease where it contributes to inflammation. After this SSP, there are conflicting data and theories regarding post-processing of MUC1 glycosylated form. Hence there is branching in the next mechanism components and we are not sure whether both branches are operating or only one of them – so ‘AND/OR’ labeling in the branches.
For Evidence: PMID:20084048, PMID:20332301, PMID:27483328
Against Evidence:
Component ID: SSP5A
Stage: Cell
SSP Class: Other
Other SSP Class: Subcellular Localization
Modifier: Altered
Ontology:
SSP Instance: MUC1 internalization
Confidence Score: 5
Comment: Due to endocytosis, MUC1 will change its location from cell surface to endosome. Hypo-glycosylated MUC1 will undergo more rapid internalization. In endosome, MUC1 will get chance to interact with intracellular toll like receptors (TLRs), including TLR3, 4, 7, 8, and 9 and TLR4 following its internalization from the cell surface.
For Evidence: PMID:10712502, PMID:23149663
Against Evidence:
Component ID: SSP5B
Stage: Protein
SSP Class: Post-Translational Modified Protein Abundance
Other SSP Class:
Modifier: NA
Ontology:
SSP Instance: MUC1 C-terminal at the cell surface
Confidence Score: 5
Comment: Extra-cellular domain of MUC1 got cleaved at the SEA domain from its cytoplasmic tail (C-terminal part) and remain at the cell surface for downstream signaling. Excessive shedding of MUC1 extracellular domain is often observed during inflammatory bowel disease.
For Evidence: PMID:27483328, PMID:10908374, PMID:11559653
Against Evidence:
Component ID: SSP6A
Stage: Cell
SSP Class: Other
Other SSP Class: Regulatory Effect
Modifier: Decreased
Ontology:
SSP Instance: Negative regulation of TLRs
Confidence Score: 3
Comment: Altered glycosylation of MUC1 can act as a ligand for TLRs and activate TLR signaling pathway. Ligand-TLR interaction initiates signaling pathways leading to the induction of several pro-inflammatory cytokines MAPKs and NF-κB which are known to induce mucin gene expression. Alternatively, these molecules can also induce TLR expression in turn regulating mucin expression thereby forming a self-perpetuating signaling loop. Some feedback loop may operate here.
For Evidence: PMID:23149663, PMID:22306702
Against Evidence:
Component ID: SSP6B1
Stage: Complex
SSP Class: Protein-Protein Complex Abundance
Other SSP Class: Protein-complex Interaction
Modifier: NA
Ontology:
SSP Instance: MUC1-IKK complex
Confidence Score: 3
Comment: MUC1 binds with I kappa beta kinase beta (IKKB) and I kappa beta kinase gamma (IKKG) to activate NF-kB pathway.
For Evidence: PMID:23149663, PMID:28052300, PMID:18037881, PMID:19706766
Against Evidence:
Component ID: SSP7
Stage: Cell
SSP Class: Other
Other SSP Class: Cell Product Abundance
Modifier: Increased
Ontology:
SSP Instance: Pro-inflammatory Chemokines, Cytokines
Confidence Score: 5
Comment:
For Evidence: PMID:18037881, PMID:19706766, PMID:28052300, PMID:23149663
Against Evidence:
Component ID: SSP6B2
Stage: Complex
SSP Class: Protein-Protein Complex Abundance
Other SSP Class: Protein-complex interaction
Modifier: NA
Ontology:
SSP Instance: MUC1 C-terminal Beta-catenin complex
Confidence Score: 3
Comment: Beta-catenin preferentially binds to the phosphorylated intracellular tail of MUC1.
For Evidence: PMID:28052300
Against Evidence:
Component ID: SSP7B2
Stage: Cell
SSP Class: Other
Other SSP Class: Defective Barrier Integrity
Modifier: NA
Ontology:
SSP Instance: Loss of adherens junction
Confidence Score: 5
Comment: Dissociation of the beta-catenin E-cadherin complex leads to the loss of adherens junction and thereby defective barrier integrity.
For Evidence: PMID:28052300, PMID:25238996
Against Evidence:
Component ID: SSP8
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 penetrance and increased inflammation will lead to increased risk of Crohn’s disease.
For Evidence: PMID:28636192, PMID:28560287
Against Evidence:
Biomarker(s) Annotations
Mechanism Module (MM) Annotations
Component ID: MM1
Mechanism Class Name: Transcription Rate
Other Mechanism Class Name:
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment: According to GTEX portal data, this SNV is an eQTL with target gene as MUC1 and the minor allele is overexpressed than the major one. There are other target genes present for this SNV. However, MUC1 is the most relevant one towards Crohn’s disease mechanism. So medium confidence level is used here.
For Evidence: PMID:20084048
Against Evidence:
Component ID: MM2
Mechanism Class Name: Translation Rate
Other Mechanism Class Name:
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Translation rate is following usual increased transcription rate.
For Evidence:
Against Evidence:
Component ID: MM3
Mechanism Class Name: Glycosylation
Other Mechanism Class Name:
Modifer: Altered
Ontology: NCIT
Mechanism Instance: Altered Glycosylation
Confidence Score: 3
Comment: This de-regulated O-linked glycosylation is well studied with respect to breast cancer or other cancers, not directly with Crohn's disease model. We are speculating that it is following the similar path - so used medium confidence here. In cancer model, overexpression of MUC1 decreases the expression of glycosyltransferases. So glycans cannot get attached to the VNTR (variable number of tandem repeats) domain of MUC1.
For Evidence: PMID:27754373, PMID:22534569, PMID:17517967
Against Evidence:
Component ID: MM4A
Mechanism Class Name: Endocytosis
Other Mechanism Class Name:
Modifer: Increased
Ontology:
Mechanism Instance: Increased Endocytosis
Confidence Score: 3
Comment: MUC1 is constantly internalized by clathrin-mediated endocytosis and recycled back to the cell surface, thus imparting capacity to carry cargo into the cell. Truncated O-glycans have about 2 fold more rate of clathrin-mediated endocytosis, compared to fully glycosylated MUC1.
For Evidence: PMID:10712502, PMID:23149663
Against Evidence:
Component ID: MM4B
Mechanism Class Name: Cleavage Rate
Other Mechanism Class Name:
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment: Structurally, MUC1 has one extracellular domain (N-terminal) of Tandem Repeats with SEA domain and one intracellular domain (C-terminal) with cytoplasmic tail. Hypo-glycosylated mucins become unstable from bacterial attack and undergoes proteolytic cleavage at the SEA domain. The mechanism of this cleavage is poorly understood and it is not established the cause of the cleavage – it may happen due to bacterial attack or due to some external factors, like changes in pH. So we used medium confidence here.
For Evidence: PMID:28052300
Against Evidence:
Component ID: MM5B
Mechanism Class Name:
Other Mechanism Class Name: Phosphorylation and signaling
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: There are several phosphorylation sites at the C-terminal sequence of MUC1. Shedding of the extracellular domain could be an activation signal that leads to phosphorylation of the intracellular domain and activation of mucin-specific signaling pathways that alter inflammatory responses. MUC1 C-terminal domain can interact with many proteins or protein complexes. Hence there is branching in the next mechanism components from MM5B and we are not sure whether both branches are operating or only one of them – so ‘AND/OR’ labeling in the branches.
For Evidence: PMID:28052300, PMID:23149663
Against Evidence:
Component ID: MM6
Mechanism Class Name:
Other Mechanism Class Name: Activation of NF-kB pathway
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: NF-kB pathway is getting activated.
For Evidence: PMID:18037881, PMID:19706766, PMID:28052300, PMID:23149663
Against Evidence:
Component ID: MM7
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:18037881, PMID:19706766, PMID:28052300, PMID:23149663
Against Evidence:
Component ID: MM6B2
Mechanism Class Name:
Other Mechanism Class Name: Destabilization of protein-complex
Modifer: NA
Ontology:
Mechanism Instance: Destabilization of E-cadherin beta-catenin complex
Confidence Score: 5
Comment: In the absence of MUC1 in epithelial cells, beta-catenin associates with E-cadherin at the plasma membrane. The beta-catenin-E-cadherin complex connects to the actin cytoskeleton and enables adherens junction formation with neighboring cells. When beta-catenin preferentially binds with phosphorylated MUC1 C-terminal, beta-catenin-E-cadherin complex gets destabilized.
For Evidence: PMID:28052300
Against Evidence:
Component ID: MM7B2
Mechanism Class Name:
Other Mechanism Class Name: Bacterial translocation
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Through a defective gut wall, more bacteria can invade in, resulting into the higher concentration of bacteria in the tissue beneath the gut wall.
For Evidence: PMID:28052300, PMID:18161747
Against Evidence:
Unknown Mechanism Module (MM) Annotations
Component ID: MM5A
Comment: MUC1 has been shown to dampen TLR signaling. However, the mechanism of how mucins are controlling TLR signaling is poorly understood. So this is black box here. PMID: 18079492, 17586693
For Evidence:
Against Evidence:
Environmental Factor Annotations
Therapeutic Interventions Annotations
Component ID: TT1
Annotation Text: TherapeuticIntervention
Comment: Restoration of barrier integrity is one of the therapeutic approaches for Crohn’s patients. treatment with sphingosine-1- phosphate (S1P), a protein which is highly expressed in the intestine and has a pivotal role in enhancing barrier function in several non-intestinal tissues, can increase levels of E- cadherin mRNA and protein in intestinal epithelial cells leading to strong E-cadherin localization to the cell–cell border.
For Evidence: PMID:25238996, PMID:20936358
Against Evidence: