{"gene":"MUCL1","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":2022,"finding":"MUCL1 drives β-catenin activation via Ser-552 phosphorylation, leading to nuclear accumulation and transcriptional activation, thereby promoting cell proliferation, invasion, migration, and EMT (increased E-cadherin, decreased vimentin) in colorectal cancer cells; MUCL1 also regulates Bcl2 and BclxL expression.","method":"siRNA knockdown in HT-29 and SW620 CRC cell lines with Western blotting, invasion/migration assays, colony formation assays","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cellular and molecular phenotypes, multiple readouts in one study, single lab","pmids":["35059735"],"is_preprint":false},{"year":2023,"finding":"miR-186-5p directly targets SBEM (MUCL1) mRNA; low miR-186-5p leads to elevated MUCL1, which activates the PI3K/AKT signaling pathway, upregulating downstream MMP1, MMP3, MMP9, CyclinD1, PCNA, and CyclinB1 to promote breast cancer cell migration, invasion, and proliferation.","method":"miR-186-5p mimic/inhibitor transfection in MDA-MB-231 cells, Western blotting, scratch/Transwell assays, PI3K activator (740Y-P) rescue experiment","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 — direct targeting validated with mimic/inhibitor and pathway rescue, single lab","pmids":["37477531"],"is_preprint":false},{"year":2025,"finding":"SBEM (MUCL1) physically interacts with dual-specificity phosphatase 16 (DUSP16) and upregulates its expression, leading to activation of the AMPK signaling pathway and conferring paclitaxel resistance in breast cancer cells.","method":"SBEM overexpression and knockdown in breast cancer cell lines, AMPK activator (AMPK activator 13) treatment, Western blotting, apoptosis assays","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2/3 — interaction and pathway activation shown with OE/KD and pharmacological rescue, single lab","pmids":["41181635"],"is_preprint":false},{"year":2026,"finding":"The sialyltransferase ST3GAL1 directly binds MUCL1 and catalyzes its sialylation, increasing MUCL1 protein stability and promoting breast cancer cell proliferation, migration, invasion, and in vivo tumor growth and lung metastasis.","method":"Co-immunoprecipitation, ST3GAL1 knockdown/overexpression, sialyltransferase inhibitor (Lith-O-Asp), MUCL1 knockdown, in vivo xenograft and metastasis models","journal":"Human cell","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding by Co-IP, enzymatic sialylation, protein stability assay, in vivo validation, multiple orthogonal methods","pmids":["41770470"],"is_preprint":false},{"year":2026,"finding":"UCHL1 (ubiquitin C-terminal hydrolase L1) stabilizes MUCL1 protein by deubiquitination; the UCHL1-MUCL1 axis promotes LPS-induced endothelial inflammation (TNF-α, IL-6, IL-8, ICAM-1 upregulation) and apoptosis in HUVECs through activation of the β-catenin/NF-κB pathway.","method":"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase assay, MUCL1/UCHL1 siRNA knockdown, MUCL1 overexpression rescue, ELISA, flow cytometry in LPS-treated HUVECs","journal":"Shock (Augusta, Ga.)","confidence":"High","confidence_rationale":"Tier 1-2 — deubiquitination mechanism validated by Co-IP, ubiquitination assay, CHX chase, pathway rescue, multiple orthogonal methods in single study","pmids":["41770679"],"is_preprint":false},{"year":2021,"finding":"MUCL1 negatively correlates with melanogenesis in epidermal melanocytes; its mucin-conforming amino acid threonine content and associated autophagy-related FOXO signaling are implicated in the regulation of melanin production and metastatic gene expression in melanoma cells.","method":"Microarray data analysis (HPA, GTEx), RNA and protein expression measurement in melanoma cells, threonine composition and FOXO signaling analysis","journal":"The British journal of dermatology","confidence":"Low","confidence_rationale":"Tier 3-4 — largely correlative with limited direct functional manipulation, single lab","pmids":["34545566"],"is_preprint":false}],"current_model":"MUCL1 is a small glycoprotein that is sialylated by ST3GAL1 (increasing its stability), deubiquitinated and stabilized by UCHL1, and promotes oncogenic signaling through β-catenin/NF-κB and PI3K/AKT pathways, interaction with DUSP16/AMPK to confer chemoresistance, and regulation of EMT markers; it is directly targeted for suppression by miR-186-5p."},"narrative":{"teleology":[{"year":2021,"claim":"Initial expression analyses linked MUCL1 to melanogenesis regulation, raising the question of whether MUCL1 has functional roles beyond its identity as a breast-specific marker.","evidence":"Microarray-based correlation of MUCL1 expression with melanin pathway genes in melanocytes and melanoma cells","pmids":["34545566"],"confidence":"Low","gaps":["Largely correlative — no direct functional manipulation of MUCL1 in melanocytes was performed","Mechanistic link between MUCL1 and FOXO/autophagy signaling not validated","Not independently replicated"]},{"year":2022,"claim":"Establishing that MUCL1 drives oncogenic signaling: knockdown revealed that MUCL1 activates β-catenin via Ser-552 phosphorylation and nuclear translocation, promoting proliferation, invasion, and EMT in colorectal cancer cells.","evidence":"siRNA knockdown in HT-29 and SW620 CRC cell lines with Western blotting, invasion/migration assays, colony formation assays","pmids":["35059735"],"confidence":"Medium","gaps":["Upstream kinase mediating β-catenin Ser-552 phosphorylation downstream of MUCL1 not identified","In vivo validation in CRC models not performed","Single-lab observation"]},{"year":2023,"claim":"The question of how MUCL1 expression is regulated was addressed by identifying miR-186-5p as a direct negative regulator of MUCL1 mRNA, with derepressed MUCL1 activating the PI3K/AKT pathway to drive breast cancer cell proliferation and invasion.","evidence":"miR-186-5p mimic/inhibitor transfection in MDA-MB-231 cells with PI3K activator rescue, Western blotting, and functional assays","pmids":["37477531"],"confidence":"Medium","gaps":["Direct luciferase reporter validation of miR-186-5p binding to MUCL1 3′-UTR not reported in this discovery","In vivo relevance of miR-186-5p–MUCL1 axis not tested","Mechanism linking MUCL1 protein to PI3K activation unknown"]},{"year":2025,"claim":"MUCL1 was shown to physically interact with DUSP16 and upregulate its expression, activating AMPK signaling and conferring paclitaxel resistance — establishing a chemoresistance mechanism through a MUCL1–phosphatase axis.","evidence":"MUCL1 overexpression/knockdown in breast cancer cell lines with AMPK activator rescue, Western blotting, apoptosis assays","pmids":["41181635"],"confidence":"Medium","gaps":["Binding interface between MUCL1 and DUSP16 not mapped","Whether DUSP16 phosphatase activity is required for the AMPK activation is untested","In vivo chemoresistance validation not performed"]},{"year":2026,"claim":"Two complementary studies resolved how MUCL1 protein stability is maintained: ST3GAL1-mediated sialylation and UCHL1-mediated deubiquitination each independently stabilize MUCL1, with functional consequences for tumor growth/metastasis and endothelial inflammation, respectively.","evidence":"Co-IP, sialylation assays, sialyltransferase inhibitor, in vivo xenograft/metastasis models (ST3GAL1 study); Co-IP, ubiquitination assay, CHX chase, siRNA rescue in LPS-treated HUVECs (UCHL1 study)","pmids":["41770470","41770679"],"confidence":"High","gaps":["Specific sialylation sites on MUCL1 not mapped","Whether sialylation and deubiquitination are coordinated or independent regulatory events is unknown","Structural basis of UCHL1–MUCL1 interaction not determined"]},{"year":null,"claim":"The direct biochemical mechanism by which MUCL1 activates β-catenin, PI3K/AKT, and AMPK signaling — whether through receptor engagement, scaffolding, or another mode — remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No receptor or direct binding partner on the cell surface identified for MUCL1 signaling initiation","No structural model of MUCL1 exists","Physiological (non-cancer) function of MUCL1 is largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,2,3]}],"complexes":[],"partners":["ST3GAL1","UCHL1","DUSP16"],"other_free_text":[]},"mechanistic_narrative":"MUCL1 is a small secreted glycoprotein that functions as an oncogenic signaling mediator by activating β-catenin, NF-κB, and PI3K/AKT pathways to promote cell proliferation, invasion, migration, and epithelial-mesenchymal transition [PMID:35059735, PMID:37477531, PMID:41770679]. MUCL1 protein stability is regulated post-translationally by ST3GAL1-mediated sialylation, which increases its half-life, and by UCHL1-mediated deubiquitination, which prevents its proteasomal degradation [PMID:41770470, PMID:41770679]. MUCL1 also physically interacts with the phosphatase DUSP16 to activate AMPK signaling and confer paclitaxel resistance in breast cancer cells [PMID:41181635]."},"prefetch_data":{"uniprot":{"accession":"Q96DR8","full_name":"Mucin-like protein 1","aliases":["Protein BS106","Small breast epithelial mucin"],"length_aa":90,"mass_kda":9.0,"function":"May play a role as marker for the diagnosis of metastatic breast cancer","subcellular_location":"Secreted; Membrane","url":"https://www.uniprot.org/uniprotkb/Q96DR8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MUCL1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SEPT8","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MUCL1","total_profiled":1310},"omim":[{"mim_id":"610857","title":"MUCIN-LIKE 1; MUCL1","url":"https://www.omim.org/entry/610857"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"breast","ntpm":3038.8},{"tissue":"skin 1","ntpm":777.3}],"url":"https://www.proteinatlas.org/search/MUCL1"},"hgnc":{"alias_symbol":["SBEM"],"prev_symbol":[]},"alphafold":{"accession":"Q96DR8","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DR8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DR8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DR8-F1-predicted_aligned_error_v6.png","plddt_mean":67.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MUCL1","jax_strain_url":"https://www.jax.org/strain/search?query=MUCL1"},"sequence":{"accession":"Q96DR8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96DR8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96DR8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DR8"}},"corpus_meta":[{"pmid":"18269587","id":"PMC_18269587","title":"Expression of small breast epithelial mucin (SBEM) protein in tissue microarrays (TMAs) of primary invasive breast cancers.","date":"2008","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/18269587","citation_count":32,"is_preprint":false},{"pmid":"20364301","id":"PMC_20364301","title":"Small breast epithelial mucin (SBEM) has the potential to be a marker for predicting hematogenous micrometastasis and response to neoadjuvant chemotherapy in breast cancer.","date":"2010","source":"Clinical & experimental metastasis","url":"https://pubmed.ncbi.nlm.nih.gov/20364301","citation_count":19,"is_preprint":false},{"pmid":"31293564","id":"PMC_31293564","title":"MAP7 and MUCL1 Are Biomarkers of Vitamin D3-Induced Tolerogenic Dendritic Cells in Multiple Sclerosis Patients.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31293564","citation_count":14,"is_preprint":false},{"pmid":"35059735","id":"PMC_35059735","title":"Targeting MUCL1 protein inhibits cell proliferation and EMT by deregulating β‑catenin and increases irinotecan sensitivity in colorectal cancer.","date":"2022","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35059735","citation_count":12,"is_preprint":false},{"pmid":"37477531","id":"PMC_37477531","title":"miRNA-186-5p inhibits migration, invasion and proliferation of breast cancer cells by targeting SBEM.","date":"2023","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/37477531","citation_count":10,"is_preprint":false},{"pmid":"34545566","id":"PMC_34545566","title":"The mucin protein MUCL1 regulates melanogenesis and melanoma genes in a manner dependent on threonine content.","date":"2021","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/34545566","citation_count":6,"is_preprint":false},{"pmid":"41770470","id":"PMC_41770470","title":"The sialyltransferase ST3GAL1 mediates MUCL1 sialylation to exacerbate breast cancer progression.","date":"2026","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/41770470","citation_count":0,"is_preprint":false},{"pmid":"41181635","id":"PMC_41181635","title":"SBEM confers paclitaxel resistance in breast cancer via DUSP16-mediated MAPK/AMPK pathway activation.","date":"2025","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/41181635","citation_count":0,"is_preprint":false},{"pmid":"41987297","id":"PMC_41987297","title":"MUCL1 in triple-negative breast cancer: a novel marker associated with the luminal androgen receptor subtype.","date":"2026","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/41987297","citation_count":0,"is_preprint":false},{"pmid":"40863740","id":"PMC_40863740","title":"An Optimized Protocol for SBEM-Based Ultrastructural Analysis of Cultured Human Cells.","date":"2025","source":"Methods and protocols","url":"https://pubmed.ncbi.nlm.nih.gov/40863740","citation_count":0,"is_preprint":false},{"pmid":"41770679","id":"PMC_41770679","title":"Integrated transcriptomic and weighted gene co-expression network analyses identify the UCHL1-MUCL1 axis as a key regulator of endothelial dysfunction in sepsis.","date":"2026","source":"Shock (Augusta, Ga.)","url":"https://pubmed.ncbi.nlm.nih.gov/41770679","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.28.656661","title":"Development of a Charge-Resistant Embedding Media for High-Performance Serial Block Face Imaging of Cells and Tissues","date":"2025-05-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.28.656661","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.08.663701","title":"Deep mapping of the <i>endomembrane system</i> of cerebellar Purkinje neurons","date":"2025-07-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.08.663701","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.06.622332","title":"Daily ultrastructural remodeling of clock neurons","date":"2024-11-07","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.06.622332","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8414,"output_tokens":1546,"usd":0.024216},"stage2":{"model":"claude-opus-4-6","input_tokens":4803,"output_tokens":1731,"usd":0.100935},"total_usd":0.125151,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"MUCL1 drives β-catenin activation via Ser-552 phosphorylation, leading to nuclear accumulation and transcriptional activation, thereby promoting cell proliferation, invasion, migration, and EMT (increased E-cadherin, decreased vimentin) in colorectal cancer cells; MUCL1 also regulates Bcl2 and BclxL expression.\",\n      \"method\": \"siRNA knockdown in HT-29 and SW620 CRC cell lines with Western blotting, invasion/migration assays, colony formation assays\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular and molecular phenotypes, multiple readouts in one study, single lab\",\n      \"pmids\": [\"35059735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-186-5p directly targets SBEM (MUCL1) mRNA; low miR-186-5p leads to elevated MUCL1, which activates the PI3K/AKT signaling pathway, upregulating downstream MMP1, MMP3, MMP9, CyclinD1, PCNA, and CyclinB1 to promote breast cancer cell migration, invasion, and proliferation.\",\n      \"method\": \"miR-186-5p mimic/inhibitor transfection in MDA-MB-231 cells, Western blotting, scratch/Transwell assays, PI3K activator (740Y-P) rescue experiment\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct targeting validated with mimic/inhibitor and pathway rescue, single lab\",\n      \"pmids\": [\"37477531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SBEM (MUCL1) physically interacts with dual-specificity phosphatase 16 (DUSP16) and upregulates its expression, leading to activation of the AMPK signaling pathway and conferring paclitaxel resistance in breast cancer cells.\",\n      \"method\": \"SBEM overexpression and knockdown in breast cancer cell lines, AMPK activator (AMPK activator 13) treatment, Western blotting, apoptosis assays\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — interaction and pathway activation shown with OE/KD and pharmacological rescue, single lab\",\n      \"pmids\": [\"41181635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The sialyltransferase ST3GAL1 directly binds MUCL1 and catalyzes its sialylation, increasing MUCL1 protein stability and promoting breast cancer cell proliferation, migration, invasion, and in vivo tumor growth and lung metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ST3GAL1 knockdown/overexpression, sialyltransferase inhibitor (Lith-O-Asp), MUCL1 knockdown, in vivo xenograft and metastasis models\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding by Co-IP, enzymatic sialylation, protein stability assay, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"41770470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"UCHL1 (ubiquitin C-terminal hydrolase L1) stabilizes MUCL1 protein by deubiquitination; the UCHL1-MUCL1 axis promotes LPS-induced endothelial inflammation (TNF-α, IL-6, IL-8, ICAM-1 upregulation) and apoptosis in HUVECs through activation of the β-catenin/NF-κB pathway.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase assay, MUCL1/UCHL1 siRNA knockdown, MUCL1 overexpression rescue, ELISA, flow cytometry in LPS-treated HUVECs\",\n      \"journal\": \"Shock (Augusta, Ga.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — deubiquitination mechanism validated by Co-IP, ubiquitination assay, CHX chase, pathway rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"41770679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MUCL1 negatively correlates with melanogenesis in epidermal melanocytes; its mucin-conforming amino acid threonine content and associated autophagy-related FOXO signaling are implicated in the regulation of melanin production and metastatic gene expression in melanoma cells.\",\n      \"method\": \"Microarray data analysis (HPA, GTEx), RNA and protein expression measurement in melanoma cells, threonine composition and FOXO signaling analysis\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3-4 — largely correlative with limited direct functional manipulation, single lab\",\n      \"pmids\": [\"34545566\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MUCL1 is a small glycoprotein that is sialylated by ST3GAL1 (increasing its stability), deubiquitinated and stabilized by UCHL1, and promotes oncogenic signaling through β-catenin/NF-κB and PI3K/AKT pathways, interaction with DUSP16/AMPK to confer chemoresistance, and regulation of EMT markers; it is directly targeted for suppression by miR-186-5p.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MUCL1 is a small secreted glycoprotein that functions as an oncogenic signaling mediator by activating β-catenin, NF-κB, and PI3K/AKT pathways to promote cell proliferation, invasion, migration, and epithelial-mesenchymal transition [PMID:35059735, PMID:37477531, PMID:41770679]. MUCL1 protein stability is regulated post-translationally by ST3GAL1-mediated sialylation, which increases its half-life, and by UCHL1-mediated deubiquitination, which prevents its proteasomal degradation [PMID:41770470, PMID:41770679]. MUCL1 also physically interacts with the phosphatase DUSP16 to activate AMPK signaling and confer paclitaxel resistance in breast cancer cells [PMID:41181635].\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Initial expression analyses linked MUCL1 to melanogenesis regulation, raising the question of whether MUCL1 has functional roles beyond its identity as a breast-specific marker.\",\n      \"evidence\": \"Microarray-based correlation of MUCL1 expression with melanin pathway genes in melanocytes and melanoma cells\",\n      \"pmids\": [\"34545566\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Largely correlative — no direct functional manipulation of MUCL1 in melanocytes was performed\",\n        \"Mechanistic link between MUCL1 and FOXO/autophagy signaling not validated\",\n        \"Not independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Establishing that MUCL1 drives oncogenic signaling: knockdown revealed that MUCL1 activates β-catenin via Ser-552 phosphorylation and nuclear translocation, promoting proliferation, invasion, and EMT in colorectal cancer cells.\",\n      \"evidence\": \"siRNA knockdown in HT-29 and SW620 CRC cell lines with Western blotting, invasion/migration assays, colony formation assays\",\n      \"pmids\": [\"35059735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Upstream kinase mediating β-catenin Ser-552 phosphorylation downstream of MUCL1 not identified\",\n        \"In vivo validation in CRC models not performed\",\n        \"Single-lab observation\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The question of how MUCL1 expression is regulated was addressed by identifying miR-186-5p as a direct negative regulator of MUCL1 mRNA, with derepressed MUCL1 activating the PI3K/AKT pathway to drive breast cancer cell proliferation and invasion.\",\n      \"evidence\": \"miR-186-5p mimic/inhibitor transfection in MDA-MB-231 cells with PI3K activator rescue, Western blotting, and functional assays\",\n      \"pmids\": [\"37477531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct luciferase reporter validation of miR-186-5p binding to MUCL1 3′-UTR not reported in this discovery\",\n        \"In vivo relevance of miR-186-5p–MUCL1 axis not tested\",\n        \"Mechanism linking MUCL1 protein to PI3K activation unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"MUCL1 was shown to physically interact with DUSP16 and upregulate its expression, activating AMPK signaling and conferring paclitaxel resistance — establishing a chemoresistance mechanism through a MUCL1–phosphatase axis.\",\n      \"evidence\": \"MUCL1 overexpression/knockdown in breast cancer cell lines with AMPK activator rescue, Western blotting, apoptosis assays\",\n      \"pmids\": [\"41181635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding interface between MUCL1 and DUSP16 not mapped\",\n        \"Whether DUSP16 phosphatase activity is required for the AMPK activation is untested\",\n        \"In vivo chemoresistance validation not performed\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Two complementary studies resolved how MUCL1 protein stability is maintained: ST3GAL1-mediated sialylation and UCHL1-mediated deubiquitination each independently stabilize MUCL1, with functional consequences for tumor growth/metastasis and endothelial inflammation, respectively.\",\n      \"evidence\": \"Co-IP, sialylation assays, sialyltransferase inhibitor, in vivo xenograft/metastasis models (ST3GAL1 study); Co-IP, ubiquitination assay, CHX chase, siRNA rescue in LPS-treated HUVECs (UCHL1 study)\",\n      \"pmids\": [\"41770470\", \"41770679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific sialylation sites on MUCL1 not mapped\",\n        \"Whether sialylation and deubiquitination are coordinated or independent regulatory events is unknown\",\n        \"Structural basis of UCHL1–MUCL1 interaction not determined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct biochemical mechanism by which MUCL1 activates β-catenin, PI3K/AKT, and AMPK signaling — whether through receptor engagement, scaffolding, or another mode — remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No receptor or direct binding partner on the cell surface identified for MUCL1 signaling initiation\",\n        \"No structural model of MUCL1 exists\",\n        \"Physiological (non-cancer) function of MUCL1 is largely uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ST3GAL1\",\n      \"UCHL1\",\n      \"DUSP16\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}