MUC1 (Mucin-1) is a heavily glycosylated type I transmembrane protein that functions as both a protective barrier at epithelial surfaces and a signaling molecule. In normal epithelia, MUC1 localizes to the apical membrane where it provides lubrication, pathogen defense, and negative regulation of inflammation via TLR signaling suppression. The cytoplasmic tail (MUC1-CT) functions as a signaling scaffold that interacts with multiple growth factor receptors, kinases, and transcription factors. In carcinomas, MUC1 is overexpressed and loses apical polarity, with MUC1-CT translocating to the nucleus where it acts as a transcriptional coregulator, modulating p53, NF-ΞΊB, and Wnt/Ξ²-catenin pathways to promote cell survival, proliferation, and metastasis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016324 apical plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: MUC1 is specifically localized to the apical plasma membrane in normal polarized epithelial cells, which is its primary and defining cellular location. This apical localization is critical for its barrier, lubrication, and pathogen defense functions. Supported by IBA phylogenetic inference and extensive literature documentation. In cancer cells, this polarity is lost and MUC1 appears across the entire cell surface, but the apical membrane remains the core physiological location. Reason: This represents the primary and most functionally significant cellular localization of MUC1 in normal epithelial cells. Apical membrane localization is essential for all of MUC1's protective barrier functions and is evolutionarily conserved across species. Supporting Evidence: file:human/MUC1/MUC1-notes.md Apical localization in normal epithelia: Prevents unwanted cell-cell and cell-ECM interactions. Steric hindrance: Bulky glycan chains impede adhesion molecule interactions. file:human/MUC1/MUC1-deep-research-openai.md See deep research file for comprehensive analysis |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The MUC1 ectodomain (N-terminal subunit) extends 200-500 nm into the extracellular space and is also released by ectodomain shedding via ADAM17/TACE cleavage. The shed ectodomain is found in serum (CA 15-3 biomarker) and extracellular fluids, so the term is correct, although the membrane-tethered form is the primary location. Reason: MUC1 has extensive extracellular presence through its shed ectodomain, so the term is correct, but the membrane-associated extracellular domain is better captured by the plasma membrane annotations. GO has since obsoleted GO:0005615 extracellular space, the replacement previously proposed here, and merged it into GO:0005576 (replaced_by), so this term is now the correct location term. Supporting Evidence: file:human/MUC1/MUC1-notes.md Extended structure projects 200-500 nm above cell surface. Ectodomain shedding: TACE (ADAM17): Constitutive and phorbol ester-stimulated shedding. Releases MUC1-N while MUC1-C remains membrane-associated. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: The MUC1 cytoplasmic tail (MUC1-CT) translocates to the nucleus where it functions as a transcriptional coregulator, interacting with p53, NF-ΞΊB, and Ξ²-catenin to regulate gene transcription. This is a well-documented cancer-associated function supported by experimental evidence (IDA) from PMID:15710329 showing chromatin localization. Reason: Nuclear localization of MUC1-CT is a critical signaling function, particularly in cancer cells. The cytoplasmic tail contains nuclear localization signals and interacts with transcription factors at chromatin. This is supported by multiple lines of experimental evidence showing functional roles in transcriptional regulation. Supporting Evidence: file:human/MUC1/MUC1-notes.md Nuclear translocation: MUC1-CT/Ξ²-catenin complex translocates to nucleus. MUC1-CT and p53 co-occupy p21 promoter. Nuclear localization signal: RLS/RRK motif interacts with nucleoporin-62, importin-Ξ²1. PMID:15710329 Chromatin immunoprecipitation assays demonstrate that MUC1 coprecipitates with p53 on the p53-responsive elements of the p21 gene promoter and coactivates p21 gene transcription. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: The MUC1 cytoplasmic tail (MUC1-CT, 72 amino acids) is present in the cytoplasm where it serves as a signaling scaffold, interacting with kinases (Src, GSK3Ξ², PKCΞ΄), adaptor proteins (Grb2), and other signaling molecules before nuclear translocation or other trafficking events. Reason: The cytoplasmic tail is a fundamental structural component of MUC1 that mediates critical signaling functions. It serves as the platform for phosphorylation events and protein-protein interactions that regulate MUC1 signaling pathways. Supporting Evidence: file:human/MUC1/MUC1-notes.md Cytoplasmic tail (MUC1-CT): 1204-1255 (72 aa). 7 conserved tyrosine residues. Multiple Ser/Thr phosphorylation sites. MUC1-CT functions as a signaling scaffold integrating multiple pathways. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: MUC1 is a type I transmembrane protein with a transmembrane domain (aa 1181-1203). In normal epithelial cells it is specifically at the apical plasma membrane, while in cancer cells it loses polarity and distributes across the entire plasma membrane. This annotation is supported by multiple lines of experimental evidence (IDA, TAS). Reason: This is a core structural feature of MUC1 as a transmembrane protein. The plasma membrane localization is fundamental to all MUC1 functions, though in normal cells this is more specifically the apical plasma membrane. Supporting Evidence: file:human/MUC1/MUC1-notes.md Transmembrane domain: 1181-1203. Loss of polarity in cancer: Present across entire cell surface (not just apical). Recycling: Endocytosis and return to plasma membrane via palmitoylation-dependent mechanism. |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Duplicate of IBA annotation for same term (GO:0016324). MUC1 apical plasma membrane localization is well-established and represents the primary physiological localization. Reason: This is a duplicate annotation with different evidence code (IEA vs IBA) for the same valid localization. Both are correct and can be retained as they come from different inference methods. Supporting Evidence: file:human/MUC1/MUC1-notes.md Apical plasma membrane: Exclusively localized, highly polarized in normal epithelial cells. |
| GO:0005515 protein binding | IPI PMID:11152665 The c-Src tyrosine kinase regulates signaling of the human D... | MODIFY | Summary: PMID:11152665 demonstrates MUC1 interaction with Src kinase (P12931), GSK3Ξ², and Ξ²-catenin. Src phosphorylates MUC1-CT at Tyr-1229 and the Src SH2 domain binds pYEKV motif. This regulates Ξ²-catenin signaling. The generic "protein binding" term should be replaced with more specific molecular function terms. Reason: The term "protein binding" is uninformative. This paper demonstrates specific signaling functions: Src kinase binding, Ξ²-catenin binding (which has its own GO term), and kinase substrate activity. These represent distinct molecular functions that should be captured with more specific GO terms. Proposed replacements: protein kinase binding beta-catenin binding Supporting Evidence: PMID:11152665 c-Src phosphorylates the MUC1 cytoplasmic domain at a YEKV motif located between sites involved in interactions with GSK3 beta and beta-catenin. |
| GO:0005515 protein binding | IPI PMID:11483589 The epidermal growth factor receptor regulates interaction o... | MODIFY | Summary: PMID:11483589 demonstrates MUC1 interaction with EGFR (P00533) and regulation of Ξ²-catenin signaling. EGFR phosphorylates MUC1-CT at Tyr-1229, modulating Ξ²-catenin binding. This represents specific receptor tyrosine kinase binding and signaling adapter functions. Reason: Generic "protein binding" should be replaced with more informative molecular function terms capturing MUC1's role as a substrate and binding partner for EGFR, a receptor tyrosine kinase. Proposed replacements: epidermal growth factor receptor binding protein kinase binding Supporting Evidence: PMID:11483589 The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin |
| GO:0005515 protein binding | IPI PMID:16888623 MUC1 oncoprotein blocks nuclear targeting of c-Abl in the ap... | MODIFY | Summary: PMID:16888623 shows MUC1 blocks nuclear targeting of c-Abl (P00519) in response to DNA damage. This demonstrates a specific protein-protein interaction that inhibits Abl nuclear import and the apoptotic response. Reason: While this demonstrates protein binding, the functional context suggests this should be captured as a more specific regulatory interaction, potentially related to DNA damage response regulation rather than generic protein binding. Proposed replacements: protein kinase binding Supporting Evidence: file:human/MUC1/MUC1-notes.md MUC1 oncoprotein blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage [PMID:16888623] PMID:16888623 Aug 3. MUC1 oncoprotein blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage. |
| GO:0005515 protein binding | IPI PMID:21258405 Galectin-3 regulates MUC1 and EGFR cellular distribution and... | MODIFY | Summary: PMID:21258405 examines Galectin-3 regulation of MUC1 and EGFR cellular distribution in pancreatic cancer cells. This demonstrates MUC1-EGFR interaction in the context of trafficking regulation. Reason: This further supports EGFR binding, which is a more informative annotation than generic protein binding. Proposed replacements: epidermal growth factor receptor binding Supporting Evidence: file:human/MUC1/MUC1-notes.md Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR downstream pathways in pancreatic cancer cells [PMID:21258405] PMID:21258405 Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR downstream pathways in pancreatic cancer cells. |
| GO:0005515 protein binding | IPI PMID:21798038 Non-cysteine linked MUC1 cytoplasmic dimers are required for... | MODIFY | Summary: PMID:21798038 demonstrates non-cysteine linked MUC1-CT dimers are required for Src recruitment and ICAM-1 binding induced cell invasion. This shows MUC1 homodimerization and binding to ICAM-1 and Src. Reason: This paper demonstrates multiple specific binding activities: protein homodimerization, ICAM-1 binding, and Src binding. These should be captured with more specific terms. Proposed replacements: identical protein binding protein kinase binding Supporting Evidence: PMID:21798038 Non-cysteine linked MUC1 cytoplasmic dimers are required for Src recruitment and ICAM-1 binding induced cell invasion. |
| GO:0005515 protein binding | IPI PMID:22962849 Cooperative interaction of MUC1 with the HGF/c-Met pathway d... | MODIFY | Summary: PMID:22962849 examines cooperative interaction of MUC1 with the HGF/c-Met pathway during hepatocarcinogenesis. This demonstrates MUC1 interaction with Met receptor tyrosine kinase (P08581). Reason: Specific receptor tyrosine kinase binding is more informative than generic protein binding. Proposed replacements: protein kinase binding Supporting Evidence: file:human/MUC1/MUC1-notes.md MET: Phosphorylates cytoplasmic tail. Cooperative interaction of MUC1 with the HGF/c-Met pathway during hepatocarcinogenesis [PMID:22962849] PMID:22962849 Cooperative interaction of MUC1 with the HGF/c-Met pathway during hepatocarcinogenesis. |
| GO:0005515 protein binding | IPI PMID:24658140 The mammalian-membrane two-hybrid assay (MaMTH) for probing ... | MODIFY | Summary: PMID:24658140 describes a mammalian-membrane two-hybrid assay (MaMTH) for probing membrane-protein interactions. This is a methods paper and the specific interaction with EGFR (P00533) supports EGFR binding. Reason: This represents EGFR binding detected by a membrane two-hybrid method. Should use more specific EGFR binding term. Proposed replacements: epidermal growth factor receptor binding Supporting Evidence: file:human/MUC1/MUC1-notes.md The mammalian-membrane two-hybrid assay (MaMTH) for probing membrane-protein interactions in human cells [PMID:24658140] PMID:24658140 The mammalian-membrane two-hybrid assay (MaMTH) for probing membrane-protein interactions in human cells. |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | MODIFY | Summary: PMID:31980649 examines extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D). This further supports MUC1-EGFR interaction in cancer signaling networks. Reason: This supports EGFR binding in the context of oncogenic KRAS signaling networks. Proposed replacements: epidermal growth factor receptor binding Supporting Evidence: file:human/MUC1/MUC1-notes.md Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D) [PMID:31980649] PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D). |
| GO:0030330 DNA damage response, signal transduction by p53 class mediator | IDA PMID:15710329 Human MUC1 oncoprotein regulates p53-responsive gene transcr... | ACCEPT | Summary: PMID:15710329 demonstrates that MUC1-CT directly binds p53 and modulates p53-responsive gene transcription following genotoxic stress. MUC1 coprecipitates with p53 on the p21 promoter and coactivates p21 transcription while attenuating Bax transcription. This shifts the p53 response from apoptosis toward growth arrest. Reason: This is a well-documented core function of MUC1-CT in cancer cells. MUC1 directly participates in p53-mediated DNA damage signaling by physically interacting with p53 at chromatin and modulating its transcriptional activity. This is supported by direct experimental evidence including chromatin immunoprecipitation and functional assays. Supporting Evidence: PMID:15710329 The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas. The present work demonstrates that MUC1 associates with the p53 tumor suppressor, and that this interaction is increased by genotoxic stress. The MUC1 cytoplasmic domain binds directly to p53 regulatory domain. file:human/MUC1/MUC1-notes.md Direct interaction: MUC1-CT binds p53 regulatory domain (aa 363-393). Chromatin localization: MUC1-CT and p53 co-occupy p21 promoter. Repression of p53 activity: MUC1-CT/KLF4 complex binds PE21 element, represses TP53 transcription. |
| GO:0031571 mitotic G1 DNA damage checkpoint signaling | IDA PMID:15710329 Human MUC1 oncoprotein regulates p53-responsive gene transcr... | ACCEPT | Summary: PMID:15710329 shows MUC1 promotes p53-dependent G1 growth arrest in response to DNA damage by coactivating p21 (CDKN1A) transcription. This represents participation in the G1 DNA damage checkpoint pathway. Reason: This annotation accurately captures MUC1's role in promoting cell cycle arrest at the G1/S checkpoint following DNA damage. By enhancing p21 transcription, MUC1 contributes to p53-mediated checkpoint activation. This is a specific and well-supported biological process annotation. Supporting Evidence: PMID:15710329 MUC1 promotes selection of the p53-dependent growth arrest response and suppresses the p53-dependent apoptotic response to DNA damage. [MUC1 coactivates p21 gene transcription, which mediates G1 arrest] file:human/MUC1/MUC1-notes.md Blocks p53-mediated cell cycle arrest and apoptosis. Confers resistance to genotoxic stress. Promotes survival of cells with DNA damage. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: This is immunofluorescence-based evidence for plasma membrane localization. MUC1 is a transmembrane protein with well-documented plasma membrane localization. This duplicates other plasma membrane annotations but with experimental imaging evidence. Reason: Direct experimental visualization of MUC1 at the plasma membrane provides independent support for this core localization. Multiple lines of evidence for the same localization strengthen the annotation. Supporting Evidence: file:human/MUC1/MUC1-notes.md Plasma membrane: Type I transmembrane protein with transmembrane domain 1181-1203. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:15710329 Human MUC1 oncoprotein regulates p53-responsive gene transcr... | ACCEPT | Summary: PMID:15710329 demonstrates that MUC1-CT coactivates p21 gene transcription by RNA polymerase II. MUC1 functions as a transcriptional coregulator that enhances p53-dependent transcription of specific target genes while repressing others (e.g., Bax). Reason: This accurately captures MUC1-CT's role as a transcriptional coregulator that positively regulates specific RNA Pol II-dependent genes. The experimental evidence demonstrates direct chromatin occupancy and transcriptional enhancement. This is a core signaling function of MUC1-CT in the nucleus. Supporting Evidence: PMID:15710329 MUC1 coprecipitates with p53 on the p53-responsive elements of the p21 gene promoter and coactivates p21 gene transcription. file:human/MUC1/MUC1-notes.md Target gene activation: Cyclin D1, c-Myc, ZEB1, Slug, Snail (via Ξ²-catenin). Target genes: Bcl-xL (anti-apoptotic), ZEB1, EZH2 (via NF-ΞΊB). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6790022 | ACCEPT | Summary: Reactome pathway annotation for "Expression of STAT3-upregulated plasma membrane proteins" includes MUC1 as a STAT3-regulated plasma membrane protein. This supports plasma membrane localization but in a specific regulatory context. Reason: This annotation correctly places MUC1 at the plasma membrane, which is its core structural location. The Reactome pathway context adds information about STAT3-mediated regulation of MUC1 expression. Supporting Evidence: file:human/MUC1/MUC1-notes.md Type I transmembrane protein with plasma membrane localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8858500 | ACCEPT | Summary: Reactome pathway annotation for "CLEC10A binds Tn-MUC1" describes interaction between C-type lectin receptor CLEC10A and tumor-associated Tn antigen on MUC1 at the plasma membrane. This represents recognition of aberrantly glycosylated MUC1. Reason: This annotation correctly places MUC1 at the plasma membrane where it interacts with CLEC10A. The pathway describes recognition of tumor-associated glycoforms of MUC1. Supporting Evidence: file:human/MUC1/MUC1-notes.md Truncated glycans exposing Tn, sTn, T antigens in cancer tissue. Plasma membrane localization. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-6786012 | KEEP AS NON CORE | Summary: Reactome pathway "CHST4 transfers SO4(2-) from PAPS to Core 2 mucins" describes sulfation of MUC1 in the Golgi lumen. MUC1 transits through the Golgi during biosynthesis where it undergoes extensive O-glycosylation and other modifications. Reason: While MUC1 does transit through the Golgi lumen during biosynthesis and post-translational modification, this is not a primary functional location. The Golgi annotations represent MUC1 as a SUBSTRATE for glycosyltransferases rather than MUC1 performing an active function. These are valid but non-core localizations representing transient biosynthetic trafficking. Supporting Evidence: file:human/MUC1/MUC1-notes.md Transit time: Median ~142 minutes ER to Golgi to surface (mouse model). Extensive O-glycosylation occurs during Golgi transit. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-5694487 | KEEP AS NON CORE | Summary: Reactome pathway "A4GNT transfers GlcNAc to core 2 mucins" describes glycosylation of MUC1 in the Golgi. Multiple Reactome glycosylation pathways annotate MUC1 to Golgi lumen as the site where O-glycan modifications occur. Reason: Same rationale as other Golgi annotations - this represents biosynthetic trafficking and modification rather than a core functional location. MUC1 is the substrate, not the enzyme. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation: Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid in Golgi. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: PMID:23533145 identified MUC1 in exosomes isolated from expressed prostatic secretions in urine using proteomic analysis. MUC1 is found in extracellular exosomes released from epithelial cells. Reason: MUC1 is legitimately found in extracellular exosomes, representing shed ectodomain or exosomal secretion. However, this is a consequence of shedding/secretion rather than a core functional location. The biological significance is uncertain - exosomal MUC1 may serve as a biomarker but is not a primary site of MUC1 function. Supporting Evidence: file:human/MUC1/MUC1-notes.md Shed ectodomain: Released by ADAM17/MT1-MMP cleavage. Isoforms 5, 7, 9, Y: Secreted into extracellular space. PMID:23533145 2013 Apr 23. In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. |
| GO:0031982 vesicle | HDA PMID:19190083 Characterization of exosome-like vesicles released from huma... | KEEP AS NON CORE | Summary: PMID:19190083 characterized exosome-like vesicles released from human tracheobronchial ciliated epithelium and identified MUC1 by proteomics. This is related to the extracellular exosome annotations. Reason: Similar to exosome annotations - MUC1 is found in secreted vesicles but this represents shedding/secretion rather than a core functional location. This is a very generic term that could apply to many cellular compartments. Supporting Evidence: file:human/MUC1/MUC1-notes.md Recycling: Endocytosis and return to plasma membrane. Vesicular trafficking for biosynthesis and endocytosis. PMID:19190083 Characterization of exosome-like vesicles released from human tracheobronchial ciliated epithelium: a possible role in innate defense. |
| GO:0005615 extracellular space | HDA PMID:16502470 Human colostrum: identification of minor proteins in the aqu... | ACCEPT | Summary: PMID:16502470 identified MUC1 in the aqueous phase of human colostrum proteome. Shed MUC1 ectodomain is found in various body fluids including serum (CA 15-3 biomarker), colostrum, and other secretions. Reason: The extracellular space is a legitimate and functionally relevant location for shed MUC1 ectodomain. Unlike the generic "extracellular region" term, this more specifically captures the soluble, secreted forms of MUC1 that serve as biomarkers and may have biological functions in body fluids. Supporting Evidence: file:human/MUC1/MUC1-notes.md CA 15-3 (Cancer Antigen 15-3): Soluble MUC1 ectodomain fragments in serum. Ectodomain shedding: ADAM17/TACE releases MUC1-N into extracellular space. PMID:16502470 Human colostrum: identification of minor proteins in the aqueous phase by proteomics. |
| GO:0033629 negative regulation of cell adhesion mediated by integrin | IDA PMID:7698991 Episialin (MUC1) overexpression inhibits integrin-mediated c... | ACCEPT | Summary: PMID:7698991 directly demonstrated that MUC1 (Episialin) overexpression inhibits integrin-mediated cell adhesion to extracellular matrix components. The large extracellular domain sterically blocks integrin-ECM interactions, creating an anti-adhesive barrier. Reason: This is a core biological function of MUC1 in normal epithelial cells, where apical MUC1 prevents unwanted adhesion. The anti-adhesive function is well-documented and represents a primary physiological role. In cancer, loss of polarity extends this anti-adhesive effect to the entire cell surface, promoting metastasis. Supporting Evidence: PMID:7698991 the integrin-mediated adhesion to extracellular matrix of transfectants of a melanoma cell line (A375), a transformed epithelial cell line (MDCK-ras-e) and a human breast epithelial cell line (HBL-100) is reduced by high levels of episialin file:human/MUC1/MUC1-notes.md Anti-Adhesive Function: Apical localization in normal epithelia: Prevents unwanted cell-cell and cell-ECM interactions. Steric hindrance: Bulky glycan chains impede adhesion molecule interactions. |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: PMID:19199708 identified MUC1 in human parotid gland exosomes by MudPIT proteomic analysis. Duplicate exosome annotation from different tissue source. Reason: Same rationale as other exosome annotations - valid but non-core localization representing secretion/shedding. Supporting Evidence: file:human/MUC1/MUC1-notes.md Extracellular exosomes contain shed MUC1 ectodomain. PMID:19199708 Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: PMID:19056867 performed large-scale proteomics and phosphoproteomics of urinary exosomes and identified MUC1. Another independent exosome identification. Reason: Same rationale as other exosome annotations - valid but non-core. Supporting Evidence: file:human/MUC1/MUC1-notes.md MUC1 found in exosomes from multiple tissue sources. PMID:19056867 2008 Dec 3. Large-scale proteomics and phosphoproteomics of urinary exosomes. |
| GO:0070062 extracellular exosome | IDA PMID:15326289 Identification and proteomic profiling of exosomes in human ... | KEEP AS NON CORE | Summary: PMID:15326289 identified and profiled exosomes in human urine and found MUC1. This has IDA evidence (direct assay) rather than HDA (high-throughput). Reason: Same rationale - exosome localization is valid but represents shedding/secretion, not core function. Supporting Evidence: file:human/MUC1/MUC1-notes.md Urinary exosomes contain MUC1 from epithelial cell shedding. PMID:15326289 Identification and proteomic profiling of exosomes in human urine. |
| GO:1902166 negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator | IDA PMID:15710329 Human MUC1 oncoprotein regulates p53-responsive gene transcr... | ACCEPT | Summary: PMID:15710329 demonstrates that MUC1 suppresses the p53-dependent apoptotic response to DNA damage while promoting growth arrest. MUC1 coactivates p21 (pro-arrest) but attenuates Bax transcription (pro-apoptotic), thereby blocking intrinsic apoptosis. Reason: This is a well-documented oncogenic function of MUC1-CT. By modulating p53 target gene selection, MUC1 shifts the cellular response from apoptosis to growth arrest, promoting survival of damaged cells. This is a core cancer-associated function supported by direct experimental evidence. Supporting Evidence: PMID:15710329 Conversely, MUC1 attenuates activation of Bax transcription. file:human/MUC1/MUC1-notes.md Consequences: Blocks p53-mediated cell cycle arrest and apoptosis. Confers resistance to genotoxic stress. Promotes survival of cells with DNA damage. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-1964505 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-5096532 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-5096537 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-6785524 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-913675 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-914005 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-914006 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-914008 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-914010 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-914017 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-977071 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-1964501 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-914012 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-914018 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-981497 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-981809 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-981814 | KEEP AS NON CORE | Summary: Reactome O-glycosylation pathway annotation. MUC1 transits through the Golgi lumen during biosynthesis where it undergoes extensive O-glycosylation by various glycosyltransferases. Reason: Golgi lumen localization represents transient biosynthetic trafficking where MUC1 serves as a substrate for glycosyltransferases. This is valid but non-core - the Golgi is not a primary functional location for MUC1. Multiple Reactome pathways annotate MUC1 to Golgi based on its role as a substrate in different O-glycan biosynthesis reactions. Supporting Evidence: file:human/MUC1/MUC1-notes.md O-Glycosylation accounts for 50-90% of total molecular mass. Initiating enzymes: Polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). Extension: Sequential addition of Gal, GalNAc, Fuc, sialic acid. Transit time: Median ~142 minutes ER to Golgi to surface. |
| GO:0000785 chromatin | IDA PMID:15710329 Human MUC1 oncoprotein regulates p53-responsive gene transcr... | ACCEPT | Summary: PMID:15710329 demonstrates MUC1-CT localization to chromatin by chromatin immunoprecipitation. MUC1 coprecipitates with p53 on the p21 promoter, showing direct chromatin association. Reason: This is a key cellular component annotation for MUC1-CT's nuclear transcriptional regulatory function. Direct chromatin association is required for MUC1-CT to function as a transcriptional coregulator. This is supported by ChIP evidence showing MUC1 at specific gene promoters. Supporting Evidence: PMID:15710329 Chromatin immunoprecipitation assays demonstrate that MUC1 coprecipitates with p53 on the p53-responsive elements of the p21 gene promoter and coactivates p21 gene transcription. file:human/MUC1/MUC1-notes.md Chromatin localization: MUC1-CT and p53 co-occupy p21 promoter. Chromatin occupancy: MUC1-CT and p65 (NF-ΞΊB) co-occupy promoters. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:15710329 Human MUC1 oncoprotein regulates p53-responsive gene transcr... | ACCEPT | Summary: PMID:15710329 shows MUC1-CT binds to the p21 promoter (a cis-regulatory region) via association with p53. MUC1-CT also binds the PE21 element to repress TP53 transcription via interaction with KLF4. Reason: MUC1-CT demonstrates sequence-specific DNA binding activity at RNA Pol II regulatory elements, though this may be mediated through transcription factor partners (p53, NF-ΞΊB, Ξ²-catenin, KLF4) rather than direct DNA contact. The ChIP evidence supports functional association with specific cis-regulatory sequences. This is a core molecular function for MUC1-CT's transcriptional regulatory role. Supporting Evidence: PMID:15710329 MUC1 coprecipitates with p53 on the p53-responsive elements of the p21 gene promoter and coactivates p21 gene transcription. file:human/MUC1/MUC1-notes.md Repression of p53 activity: MUC1-CT/KLF4 complex binds PE21 element, represses TP53 transcription. MUC1-CT and p65 co-occupy promoters. |
| GO:0002039 p53 binding | IPI PMID:15710329 Human MUC1 oncoprotein regulates p53-responsive gene transcr... | ACCEPT | Summary: PMID:15710329 demonstrates direct binding between MUC1 cytoplasmic domain and p53 regulatory domain (aa 363-393). This interaction is increased by genotoxic stress and modulates p53 transcriptional activity. Reason: This is a core molecular function of MUC1-CT. Direct p53 binding is central to MUC1's role in DNA damage response, cell cycle regulation, and apoptosis suppression. This is well-documented with multiple lines of evidence including co-immunoprecipitation, ChIP, and functional assays. Supporting Evidence: PMID:15710329 The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas. The present work demonstrates that MUC1 associates with the p53 tumor suppressor, and that this interaction is increased by genotoxic stress. The MUC1 cytoplasmic domain binds directly to p53 regulatory domain. file:human/MUC1/MUC1-notes.md Direct interaction: MUC1-CT binds p53 regulatory domain (aa 363-393). MUC1-CT and p53 co-occupy p21 promoter. |
| GO:0003712 transcription coregulator activity | IDA PMID:15710329 Human MUC1 oncoprotein regulates p53-responsive gene transcr... | ACCEPT | Summary: PMID:15710329 demonstrates MUC1-CT functions as a transcriptional coregulator, coactivating p21 transcription while repressing Bax. MUC1-CT also coactivates transcription with NF-ΞΊB, Ξ²-catenin, and estrogen receptor. Reason: This is a core molecular function of MUC1-CT in the nucleus. MUC1-CT does not directly bind DNA alone but functions as a coregulator that modulates the activity of multiple transcription factors. This represents the primary molecular mechanism by which MUC1-CT influences gene expression. Extensively supported by literature. Supporting Evidence: PMID:15710329 MUC1 coprecipitates with p53 on the p53-responsive elements of the p21 gene promoter and coactivates p21 gene transcription. Conversely, MUC1 attenuates activation of Bax transcription. file:human/MUC1/MUC1-notes.md Transcription factors: TP53, ESR1 (estrogen receptor Ξ±), KLF4, NF-ΞΊB p65. MUC1-CT functions as a signaling scaffold and transcriptional coregulator. |
| GO:0010944 negative regulation of transcription by competitive promoter binding | IDA PMID:15710329 Human MUC1 oncoprotein regulates p53-responsive gene transcr... | ACCEPT | Summary: PMID:15710329 shows MUC1-CT represses Bax transcription while coactivating p21, suggesting differential regulation of p53 target genes. MUC1-CT/KLF4 complex also competes for binding to the PE21 element to repress TP53 transcription. Reason: This captures MUC1-CT's ability to negatively regulate specific genes through competitive binding mechanisms. By occupying regulatory elements with transcription factors, MUC1-CT can block access of other regulatory factors or modulate the transcriptional outcome. This is a specific and well-supported regulatory mechanism. Supporting Evidence: PMID:15710329 MUC1 attenuates activation of Bax transcription. file:human/MUC1/MUC1-notes.md Repression of p53 activity: MUC1-CT/KLF4 complex binds PE21 element, represses TP53 transcription. |
| GO:0005886 plasma membrane | TAS PMID:1697589 Molecular cloning and expression of human tumor-associated p... | ACCEPT | Summary: PMID:1697589 is the original molecular cloning paper for human MUC1, describing it as a tumor-associated polymorphic epithelial mucin. This paper established MUC1 as a transmembrane protein localized to the plasma membrane. Reason: This is a traceable author statement from the original MUC1 cloning paper establishing its plasma membrane localization. This is a fundamental structural annotation for MUC1 as a type I transmembrane protein. Supporting Evidence: file:human/MUC1/MUC1-notes.md Type I transmembrane protein with transmembrane domain 1181-1203. Plasma membrane is the primary structural location. PMID:1697589 Molecular cloning and expression of human tumor-associated polymorphic epithelial mucin. |
| GO:0005198 structural molecule activity | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:7698991 Episialin (MUC1) overexpression inhibits integrin-mediated cell adhesion to extracellular matrix components. file:human/MUC1/MUC1-notes.md Extended structure projects 200-500 nm above cell surface. Anti-Adhesive Function: Apical localization in normal epithelia prevents unwanted cell-cell and cell-ECM interactions. Steric hindrance: Bulky glycan chains impede adhesion molecule interactions. |
| GO:0050830 defense response to Gram-positive bacterium | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:7698991 Episialin (MUC1) overexpression inhibits integrin-mediated cell adhesion to extracellular matrix components. file:human/MUC1/MUC1-notes.md Extended structure projects 200-500 nm above cell surface. Anti-Adhesive Function: Apical localization in normal epithelia prevents unwanted cell-cell and cell-ECM interactions. Steric hindrance: Bulky glycan chains impede adhesion molecule interactions. |
| GO:0005102 signaling receptor binding | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: file:human/MUC1/MUC1-notes.md Negative regulator of TLR signaling: Interacts with TLR2, TLR3, TLR4, TLR5, TLR7, TLR9. TLR5 mechanism: MUC1-CT blocks MyD88 recruitment upon flagellin binding. TLR3 mechanism: MUC1-CT prevents TRIF adapter binding, suppresses IFN-Ξ² response. |
| GO:0034122 negative regulation of toll-like receptor signaling pathway | NAS | NEW | Summary: Added to align core_functions with existing annotations. Liu et al. 2023 (PMID:37880668) provides direct experimental support in airway epithelium, showing MUC1-CT physically interacts with TLR4 by co-immunoprecipitation in BEAS-2B cells and that MUC1 knockdown increases TLR4-MyD88 binding and downstream NF-ΞΊB activation, with consequent NLRP3 inflammasome-mediated pyroptosis. Reason: Core function term not present in existing_annotations. Supporting Evidence: file:human/MUC1/MUC1-notes.md Negative regulator of TLR signaling: Interacts with TLR2, TLR3, TLR4, TLR5, TLR7, TLR9. TLR5 mechanism: MUC1-CT blocks MyD88 recruitment upon flagellin binding. TLR3 mechanism: MUC1-CT prevents TRIF adapter binding, suppresses IFN-Ξ² response. PMID:37880668 MUCl-CT interacted with TLR4, and the interaction between TLR4 and MyD88 was significantly increased after MUCl-siRNA transfection. |
| GO:0060070 canonical Wnt signaling pathway | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:11152665 The results demonstrate that the c-Src SH2 domain binds directly to pYEKV and inhibits the interaction between MUC1 and GSK3 beta. file:human/MUC1/MUC1-notes.md Nuclear translocation: MUC1-CT/Ξ²-catenin complex translocates to nucleus. Target gene activation: Cyclin D1, c-Myc, ZEB1, Slug, Snail (via Ξ²-catenin). Phosphorylation-dependent: Tyr-1229 phosphorylation increases Ξ²-catenin binding. Ser-1227 phosphorylation decreases Ξ²-catenin binding. |
| GO:0045893 positive regulation of DNA-templated transcription | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: file:human/MUC1/MUC1-notes.md Nuclear interaction: MUC1-CT binds NF-ΞΊB p65 in nucleus. Mechanism: Blocks p65 interaction with IΞΊBΞ± inhibitor. Target genes: Bcl-xL (anti-apoptotic), ZEB1, EZH2 (EMT/stemness). Chromatin occupancy: MUC1-CT and p65 co-occupy promoters. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | NAS | NEW | Summary: Added to align core_functions with existing annotations. Term updated from obsolete GO:0051092 to GO:0043123. Daimon et al. 2024 (PMID:38182558) provide additional support by demonstrating an NF-ΞΊB/MUC1-C auto-inductive feedback loop required for antioxidant gene expression and ferroptosis resistance. Reason: Core function term not present in existing_annotations. Original term GO:0051092 was obsoleted. Supporting Evidence: file:human/MUC1/MUC1-notes.md Nuclear interaction: MUC1-CT binds NF-ΞΊB p65 in nucleus. Mechanism: Blocks p65 interaction with IΞΊBΞ± inhibitor. Target genes: Bcl-xL (anti-apoptotic), ZEB1, EZH2 (EMT/stemness). Chromatin occupancy: MUC1-CT and p65 co-occupy promoters. PMID:38182558 We demonstrate that SAL suppresses MUC1-C expression by disrupting a NF-ΞΊB/MUC1-C auto-inductive circuit that is necessary for ferroptosis resistance. |
| GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:11483589 The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin. file:human/MUC1/MUC1-notes.md Growth factor receptors: EGFR, HER2/ERBB2, ERBB3, ERBB4, MET, PDGFRB, FGFR3, IGF1R. MUC1 expression inhibits degradation of ligand-activated ErbB1 following growth factor stimulation, thereby increasing cellular pools of active receptor and prolonging mitogenic signaling. |
| GO:0008283 cell population proliferation | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:11483589 The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin. file:human/MUC1/MUC1-notes.md Growth factor receptors: EGFR, HER2/ERBB2, ERBB3, ERBB4, MET, PDGFRB, FGFR3, IGF1R. MUC1 expression inhibits degradation of ligand-activated ErbB1 following growth factor stimulation, thereby increasing cellular pools of active receptor and prolonging mitogenic signaling. |
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Download this section (compressed HTML)Q: What are the specific structural requirements for MUC1-CT palmitoylation that enable its lipid raft association and membrane recycling?
Suggested experts: Cell biologists specializing in protein trafficking, Structural biologists studying palmitoylation
Q: How do different VNTR polymorphisms (21-125 repeats) quantitatively affect MUC1's barrier function and pathogen defense capabilities in vivo?
Suggested experts: Immunologists studying mucosal immunity, Geneticists studying MUC1 polymorphisms
Q: What determines whether MUC1-CT acts as a p53 activator versus inhibitor in different cellular contexts, and what is the role of tyrosine phosphorylation in this switch?
Suggested experts: Cancer biologists studying p53 regulation, Signal transduction researchers
Q: How do the different O-glycosylation patterns (normal vs cancer) mechanistically affect MUC1's protein-protein interactions and signaling capabilities?
Suggested experts: Glycobiologists specializing in mucin glycosylation, Structural biologists
Q: What is the precise mechanism by which MUC1-CT suppresses different TLR pathways, and are there tissue-specific differences in this regulation?
Suggested experts: Immunologists studying TLR signaling, Epithelial biologists
Q: How does MUC1 mechanistically contribute to ADTKD2 pathogenesis, and what cellular processes are disrupted by the frameshift mutations?
Suggested experts: Nephrologists specializing in tubulointerstitial disease, Kidney development biologists
Experiment: Determine crystal structure of MUC1-CT in complex with Ξ²-catenin and p53 to understand competitive binding and nuclear complex formation
Hypothesis: MUC1-CT binds Ξ²-catenin and p53 through overlapping or adjacent interaction surfaces, and phosphorylation alters binding preferences
Type: structural analysis
Experiment: Use CRISPR to generate cells with VNTR alleles of defined lengths (e.g., 21, 41, 85, 125 repeats) and measure pathogen binding, shedding efficiency, and TLR signaling suppression
Hypothesis: Longer VNTR alleles provide better pathogen defense through enhanced steric hindrance and releasable decoy function
Type: genetic manipulation
Experiment: Perform time-resolved mass spectrometry to map the complete phosphorylation dynamics of MUC1-CT tyrosines upon EGFR, PDGFRB, and Src activation, and correlate with protein interaction changes
Hypothesis: Different kinases create distinct phosphorylation codes that recruit specific signaling complexes (Grb2 vs Ξ²-catenin vs PI3K)
Type: phosphoproteomics
Experiment: Use proximity labeling (BioID/APEX) to identify the complete MUC1-CT interactome in normal epithelial cells versus cancer cells, comparing apical membrane, cytoplasmic, and nuclear compartments
Hypothesis: MUC1-CT interactome shifts from structural/trafficking proteins in normal cells to signaling/transcriptional proteins in cancer cells
Type: interactomics
Experiment: Measure the effect of specific O-glycosylation patterns (controlled via glycosyltransferase knockout/overexpression) on MUC1 ectodomain shedding kinetics, drug penetration, and immune recognition
Hypothesis: Aberrant cancer-associated glycosylation (short glycans) accelerates shedding, creates drug resistance barrier, and generates tumor-specific epitopes
Type: glycobiology
Experiment: Use kidney organoids derived from ADTKD2 patient iPSCs to identify the molecular pathways disrupted by MUC1 frameshift mutations and test therapeutic interventions
Hypothesis: Mutant MUC1 accumulates in ER causing ER stress and activating fibrotic pathways in tubular epithelial cells
Type: disease modeling
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