{"gene":"CEMIP","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2013,"finding":"KIAA1199 (CEMIP) is a hyaluronan-binding protein that mediates hyaluronan depolymerization independently of CD44 and HYAL enzymes. Specific HA binding was demonstrated in glycosaminoglycan-binding assays; knockdown abolished HA degradation by skin fibroblasts; transfection of KIAA1199 cDNA conferred HA catabolism via an endo-β-N-acetylglucosaminidase-dependent mechanism through the clathrin-coated pit pathway.","method":"Glycosaminoglycan-binding assay, siRNA knockdown, cDNA transfection, clathrin pathway inhibition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro assays (binding assay, KD, gain-of-function), mechanistic pathway defined, replicated in multiple cell types including disease specimens","pmids":["23509262"],"is_preprint":false},{"year":2013,"finding":"KIAA1199 localizes to the endoplasmic reticulum where it forms a stable complex with the chaperone BiP. An ER-retention motif within KIAA1199 is required for ER localization, BiP interaction, and enhanced cell migration. KIAA1199 mediates ER calcium leakage, and the resultant increase in cytosolic calcium activates protein kinase C alpha (PKCα), promoting cell migration.","method":"SNAP-tag pull-down assay, confocal microscopy, FRET-based calcium measurement, spectrofluorometry, Western blotting, mutagenesis of ER-retention motif, siRNA knockdown, in vivo xenograft","journal":"Journal of the National Cancer Institute","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (pulldown, FRET, mutagenesis, imaging), both loss-of-function and gain-of-function with defined molecular mechanism","pmids":["23990668"],"is_preprint":false},{"year":2013,"finding":"The N-terminal 30 amino acids of KIAA1199 function as a cleavable signal sequence required for proper intracellular trafficking and KIAA1199-mediated HA depolymerization. Deletion of the N-terminal portion results in altered intracellular trafficking and loss of HA depolymerization activity.","method":"N-terminal deletion constructs, intracellular trafficking assays, HA depolymerization assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — functional mutagenesis combined with trafficking and enzymatic assays, single lab","pmids":["24269685"],"is_preprint":false},{"year":2013,"finding":"KIAA1199 is secreted into the extracellular environment by colon cancer cells. It is found in the perinuclear ER and at the cell membrane. Co-immunoprecipitation confirmed interaction with the cell membrane receptor ephrin A2 and with the ER receptor ITPR3 (a key Ca2+ signaling component), linking KIAA1199 to Ca2+ and Wnt/CTNNB1 signaling.","method":"Immunostaining, mass spectrometry proteomics, co-immunoprecipitation, transcriptomics","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP confirmed specific interactions with EphA2 and ITPR3, supported by proteomics; single lab","pmids":["23936024"],"is_preprint":false},{"year":2013,"finding":"Murine Kiaa1199 (mKiaa1199) binds hyaluronan specifically and mediates HA depolymerization via the clathrin-coated pit pathway, consistent with the human ortholog, though slight differences exist in minimum HA degradate sizes.","method":"cDNA transfection in cells, glycosaminoglycan-binding assay, HA catabolism assay, clathrin pathway inhibition","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional replication in murine ortholog using same experimental framework as human studies; single lab","pmids":["24251095"],"is_preprint":false},{"year":2014,"finding":"KIAA1199 is a BCL-3- and p65-dependent NF-κB target gene. It binds Plexin A2 and protects cells from Semaphorin 3A-mediated cell death by promoting EGFR stability and signaling. KIAA1199 is an EGFR-binding protein and its deficiency impairs EGF-dependent Src, MEK1, and ERK1/2 phosphorylations, thereby promoting EGF-mediated EMT.","method":"ChIP, co-immunoprecipitation, Western blotting, siRNA knockdown, overexpression, cell death assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction studies (Co-IP for EGFR and PlexinA2 binding), ChIP for transcriptional regulation, multiple orthogonal functional readouts","pmids":["25366117"],"is_preprint":false},{"year":2014,"finding":"KIAA1199 interacts with glycogen phosphorylase kinase β-subunit (PHKB) via its C-terminal region, as demonstrated by pull-down assay. Under serum-free conditions, KIAA1199 also interacts with glycogen phosphorylase brain form (PYGB). These interactions promote glycogen breakdown and cancer cell survival.","method":"MBP fusion protein pull-down assay, retroviral overexpression, glycogen breakdown assays, cell survival assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pull-down with defined C-terminal domain plus functional glycogen assay; single lab, no reciprocal Co-IP","pmids":["25051373"],"is_preprint":false},{"year":2015,"finding":"HIF-2α (but not HIF-1α) directly binds to the hypoxia response element within the CEMIP promoter, driving CEMIP transcription under hypoxic conditions. CEMIP is a downstream effector of HIF-2α-mediated cell migration. CEMIP expression negatively correlates with histone demethylase Jarid1A; low oxygen inhibits Jarid1A, increasing H3K4me3 at the CEMIP promoter.","method":"ChIP, promoter binding assay, siRNA knockdown of HIF-1α vs HIF-2α, H3K4me3 chromatin analysis, cell migration assay","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct promoter binding shown by ChIP, isoform-specific knockdown discriminating HIF-1α vs HIF-2α, multiple orthogonal methods","pmids":["26009875"],"is_preprint":false},{"year":2015,"finding":"TGF-β1, bFGF, EGF, and PDGF-BB commonly enhance total HA in skin fibroblasts through HAS up-regulation, but molecular size of newly produced HA depends on HYBID/KIAA1199 expression. TGF-β1 suppresses HYBID expression via PI3K-Akt signaling and stimulates HAS1/2 via MAPK/Smad, resulting in high molecular weight HA. In arthritic synovial fibroblasts, inefficient TGF-β1-mediated suppression of HYBID leads to accumulation of low-MW HA.","method":"siRNA knockdown, signaling pathway inhibitors (PI3K, MAPK, Smad), HA size-exclusion chromatography, gene expression analysis, human tissue correlation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection of signaling pathways with specific inhibitors, validated in multiple cell types and clinical specimens","pmids":["26518873"],"is_preprint":false},{"year":2016,"finding":"Crohn's Disease fibroblasts overproduce KIAA1199 primarily through an IL-6-driven autocrine mechanism. IL-6 stimulation increases KIAA1199 deposition in the ECM. siRNA silencing of KIAA1199 abrogated HA degradation by colon fibroblasts. Antibody blockade of IL-6 receptors decreased KIAA1199 protein in the ECM.","method":"siRNA knockdown, IL-6 receptor antibody blockade, HA degradation biochemical assay, immunoblot, immunostaining of clinical specimens","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA, antibody blockade, biochemical HA assay), patient specimens, clear mechanistic link","pmids":["27981209"],"is_preprint":false},{"year":2017,"finding":"KIAA1199 expression in cancer cells is induced by pro-inflammatory cytokine IL-1β and suppressed by the COX-2 inhibitor NS-398. Forced expression of KIAA1199 increases low-molecular-weight HA in conditioned medium. siRNA knockdown decreases cell migration and proliferation in pancreatic cancer.","method":"siRNA knockdown, gene transduction (overexpression), IL-1β stimulation, NS-398 treatment, HA molecular weight analysis of conditioned medium","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — gain- and loss-of-function with defined cytokine regulation; single lab; HA size analysis links KIAA1199 to LMW-HA production","pmids":["28179576"],"is_preprint":false},{"year":2017,"finding":"KIAA1199 interacts with WBP11 (WW domain binding protein 11) and PTP4A3 (protein tyrosine phosphatase type IVA, member 3). This binding activates FGFR4/Wnt/β-catenin and EGFR signaling pathways to regulate E-cadherin and N-cadherin expression. Ectopic expression of WBP11 or PTP4A3 blocked KIAA1199-stimulated cell proliferation and migration.","method":"Co-immunoprecipitation, overexpression/knockdown, Western blotting, in vitro and in vivo functional assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP identifies binding partners, functional rescue experiments; single lab","pmids":["30626935"],"is_preprint":false},{"year":2017,"finding":"KIAA1199 promotes Nrg1-dependent MEK1 and ERK1/2 activation in Schwann cells. In the absence of KIAA1199, SC dedifferentiation is impaired: cJun and negative regulators of myelination are decreased while Krox20 is elevated, driving a pro-myelinating phenotype. KIAA1199-deficient SCs show lower myelin clearance and increased myelination capacity.","method":"RNA interference, conditional Cre-lox knockout mice (tamoxifen-inducible), Nrg1 stimulation, Western blotting for MEK/ERK pathway components, myelination assays","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Strong — both RNAi and conditional in vivo knockout with multiple molecular and cellular readouts; defines pathway position in MEK/ERK signaling in Schwann cells","pmids":["28699206"],"is_preprint":false},{"year":2018,"finding":"CEMIP localizes to endosomes where it acts as a scaffold protein binding MEK1, sustaining ERK1/2 activation in BRAF-mutated MEK1-inhibitor-resistant colorectal cancers. CEMIP expression is induced by β-catenin- and FRA-1-dependent Wnt pathway activation. CEMIP-dependent ERK1/2 signaling maintains c-Myc protein levels, providing metabolic advantage to resistant cells.","method":"siRNA knockdown, co-immunoprecipitation (CEMIP–MEK1 interaction), endosomal fractionation, Western blotting, intestinal organoids, in vivo mouse models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — endosomal localization plus Co-IP of MEK1, functional epistasis in organoids and in vivo, multiple orthogonal methods","pmids":["29915160"],"is_preprint":false},{"year":2018,"finding":"The AMPK/GSK3β/β-catenin cascade drives CEMIP overexpression in anoikis-resistant prostate cancer cells. CEMIP promotes migration, invasion, and metabolic reprogramming via PDK4 upregulation, increasing pyruvate and lactate production. CRISPR knockout of CEMIP reversed these effects and reduced MMP2, VEGF, PDK4, and lactate dehydrogenase A expression.","method":"CRISPR/Cas9 knockout, Western blotting, metabolic assays (pyruvate, lactate, ATP), genome microarray, migration/invasion assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with metabolic and functional readouts, pathway defined; single lab","pmids":["29505302"],"is_preprint":false},{"year":2018,"finding":"KIAA1199 interacts with protein phosphatase 2A (PP2A) through its C-terminal domain and increases PP2A phosphatase activity. Downstream, stathmin (a microtubule-destabilizing protein) is dephosphorylated, leading to microtubule destabilization and enhanced cell motility. Paclitaxel (microtubule-stabilizing drug) prevents KIAA1199-induced microtubule destabilization.","method":"Co-immunoprecipitation (KIAA1199-PP2A), phosphatase activity assays, stathmin phosphorylation Western blotting, microtubule polymerization assays, paclitaxel rescue, in vivo orthotopic model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, enzymatic activity assay, pharmacological rescue with paclitaxel, in vivo validation; multiple orthogonal methods","pmids":["30202098"],"is_preprint":false},{"year":2018,"finding":"HYBID/KIAA1199 is indispensable for HA depolymerization in skin fibroblasts; TMEM2 knockdown unexpectedly enhanced HA depolymerization rather than reducing it, demonstrating that TMEM2 is not involved as a catalytic hyaluronidase in HYBID-mediated HA depolymerization. TGF-β1 coordinately suppresses HYBID expression and upregulates TMEM2 expression.","method":"siRNA knockdown of HYBID and TMEM2 separately, HA depolymerization assay, TGF-β1 and growth factor treatment, multiple cell lines","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional siRNA knockdown with biochemical HA assay, multiple cell types; single lab","pmids":["30241936"],"is_preprint":false},{"year":2018,"finding":"CEMIP upregulates BiP transcript and protein levels by mediating activation of the BiP promoter in breast cancer cells. CEMIP overexpression confers protective adaptations to hypoxia (decreased apoptosis, activated autophagy, increased glucose uptake). BiP signals downstream of CEMIP to modulate cellular resistance to hypoxia; reducing BiP in CEMIP-expressing cells sensitized cells to hypoxia and caused tumor regression in vivo.","method":"BiP promoter reporter assay, siRNA knockdown, overexpression, hypoxia treatment, apoptosis/autophagy assays, glucose uptake assay, in vivo xenograft","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — promoter assay plus functional epistasis (BiP knockdown in CEMIP-expressing cells) with in vivo validation; single lab","pmids":["31303964"],"is_preprint":false},{"year":2019,"finding":"CEMIP protein is elevated in exosomes from brain metastatic cancer cells. Uptake of CEMIP+ exosomes by brain endothelial and microglial cells induces endothelial cell branching and inflammation in the perivascular niche, upregulating pro-inflammatory cytokines (Ptgs2, Tnf, Ccl/Cxcl) that promote brain vascular remodeling. CEMIP depletion in tumor cells impaired brain metastasis and tumor-vasculature association, phenotypes rescued by pre-conditioning the brain with CEMIP+ exosomes.","method":"Proteomic analysis of exosomes, CEMIP depletion (genetic), exosome uptake experiments, brain endothelial/microglial co-culture, cytokine profiling, in vivo brain metastasis model with exosome pre-conditioning","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — exosome proteomics, genetic depletion with rescue by exosome pre-conditioning, in vivo validation, multiple cell type targets and cytokine readouts","pmids":["31685984"],"is_preprint":false},{"year":2019,"finding":"CEMIP promotes fibrosis-like transdifferentiation of OA chondrocytes into 'chondro-myo-fibroblasts' expressing α-SMA and type III collagen. CEMIP regulates β-catenin protein level, is required for chondrocyte proliferation, and promotes TGFβ signaling via the p-Smad2/3 (Alk5/PAI-1) pathway. CEMIP expression is induced by the pSmad1/5 (Alk1) pathway.","method":"siRNA knockdown, high-throughput RNA sequencing, Western blotting, in vitro chondrocyte dedifferentiation model, human and mouse OA tissue analysis, in situ co-localization","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RNA-seq and functional assays identify TGFβ pathway connections; pathway assignment via siRNA; single lab","pmids":["30718510"],"is_preprint":false},{"year":2019,"finding":"KIAA1199 promotes osteoblastic stem cell (hMSC) migration. KIAA1199-deficient hMSCs show changes in cell morphology, reduced F-actin polymerization, and altered phosphorylation of cofilin1 (CFL1) and LIM-domain kinase 1 (LIMK1). KIAA1199 activates P38 kinase and its associated changes in Wnt signaling; impaired Wnt/TCF reporter activity in KIAA1199-deficient hMSCs was rescued by KIAA1199 treatment.","method":"shRNA knockdown, scratch assay, trans-well migration, F-actin staining, Western blotting (pCFL1, pLIMK1, DSTN), TCF-reporter assay, P38 kinase assay, rescue with recombinant KIAA1199","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple molecular readouts plus signaling rescue; single lab, no independent replication","pmids":["30755597"],"is_preprint":false},{"year":2020,"finding":"Cemip is the major inducible gene responsible for hyaluronan catabolism in mouse dermis upon S. aureus infection. Cemip-/- mice failed to digest hyaluronan and had significantly less infection after intradermal S. aureus challenge. Stabilization of large-MW HA in Cemip-/- mice enabled increased cathelicidin antimicrobial peptide (Camp) expression, partly through enhanced differentiation of preadipocytes to adipocytes. Cemip-/- mice also showed greater IL-6 expression and neutrophil infiltration.","method":"Cemip knockout mice (genetic), intradermal S. aureus challenge, HA molecular weight analysis, Camp/antimicrobial peptide expression, histology (Pref1, PPARγ, Adipoq markers), IL-6 and neutrophil quantification","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout model with infectious challenge, multiple mechanistic readouts linking HA degradation to adipocyte differentiation and antimicrobial defense; orthogonal methods","pmids":["31914398"],"is_preprint":false},{"year":2020,"finding":"HYBID/KIAA1199 knockout mice show decreased dendritic spine density in the dentate gyrus granule cells, accompanied by HA accumulation and decreased doublecortin-positive immature neurons in the dentate gyrus, suggesting HYBID-mediated HA degradation is critical for synaptic formation and cognitive function.","method":"Hybid knockout mice, Golgi-Cox staining (dendritic spine density), HA staining, doublecortin immunostaining","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with cellular and molecular phenotypes; single lab, no independent replication","pmids":["30060951"],"is_preprint":false},{"year":2020,"finding":"Histamine increases HA degradation in skin fibroblasts by up-regulating HYBID/KIAA1199 and down-regulating HAS2. The histamine H1 receptor mediates these effects. HYBID up-regulation requires protein kinase Cδ signaling, while HAS2 suppression requires PI3K-Akt signaling downstream of H1 receptor.","method":"Histamine H1 agonist/antagonist, PKCδ inhibitor, PI3K-Akt inhibitor, HA molecular weight analysis, HYBID/HAS2 expression analysis, immunohistochemistry in human skin biopsies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological dissection of separate signaling pathways with specific inhibitors, validated in human tissue; multiple orthogonal methods","pmids":["31949043"],"is_preprint":false},{"year":2021,"finding":"Secreted KIAA1199 mediates extracellular HA degradation by attaching to the cell membrane of RA fibroblast-like synoviocytes via its G8 domain binding to ANXA1. In vivo, KIAA1199 knockout mice showed greater resistance to collagen-induced arthritis, partially reversed by intra-articular injection of full-length but not G8-deleted KIAA1199. NF-κB activation by IL-6 through PI3K/Akt signaling is the main pathway inducing KIAA1199 expression in RA FLS.","method":"Anti-KIAA1199 mAb treatment, KIAA1199 KO mice, collagen-induced arthritis model, intra-articular gene injection (WT vs G8-deleted mutant), cell membrane binding assay, HA degradation assay, NF-κB/PI3K/Akt inhibitor analysis","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-specific mutant rescue experiment defines G8/ANXA1 interaction as mechanistically required; in vivo KO with rescue, multiple orthogonal methods","pmids":["33473125"],"is_preprint":false},{"year":2021,"finding":"CEMIP acts as a novel adaptor protein for O-GlcNAc transferase (OGT). CEMIP interacts with OGT and β-catenin, leading to elevated O-GlcNAcylation of β-catenin and enhanced β-catenin nuclear translocation. Nuclear β-catenin then enhances CEMIP transcription in a reciprocal positive feedback loop and upregulates glutaminase 1, SLC1A5, and SLC38A2 (glutamine transporters) to promote glutamine metabolic reprogramming and CRC metastasis.","method":"Co-immunoprecipitation (CEMIP-OGT-β-catenin complex), O-GlcNAcylation assay, β-catenin nuclear fractionation, transcriptional reporter, in vivo CRC metastasis model with combinational inhibition","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP defines trimeric complex, O-GlcNAcylation biochemically demonstrated, reciprocal regulation validated with in vivo readout; multiple orthogonal methods","pmids":["34608265"],"is_preprint":false},{"year":2022,"finding":"ATF4 triggers CEMIP transcription during ECM detachment, and elevated CEMIP promotes PKCα membrane translocation, leading to serine-70 phosphorylation of Bcl-2. This phosphorylation dissociates the Bcl-2/Beclin1 complex, inducing protective autophagy and anoikis resistance in prostate cancer cells.","method":"siRNA knockdown, Western blotting (pBcl-2 Ser70, Beclin1 complex), PKCα translocation assay, autophagy flux assay, ATF4 ChIP/promoter analysis, in vivo metastasis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mechanistic chain defined (ATF4→CEMIP→PKCα→pBcl-2→Beclin1 dissociation→autophagy), multiple Western readouts; single lab","pmids":["35013120"],"is_preprint":false},{"year":2022,"finding":"CEMIP promotes ferroptosis resistance during ECM detachment by promoting cystine uptake. Mechanistically, CEMIP interacts with ITPR3 to modulate ER calcium leakage, activating CaMKII, which phosphorylates NRF2 and promotes its nuclear localization, leading to elevated SLC7A11 transcription (a cystine/glutamate antiporter). Silencing CEMIP abolishes cystine uptake promotion and ferroptosis resistance.","method":"Co-immunoprecipitation (CEMIP-ITPR3), CaMKII activity assay, NRF2 nuclear fractionation, SLC7A11 expression analysis, cystine uptake assay, ferroptosis assays, siRNA knockdown","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP identifies CEMIP-ITPR3 interaction, mechanistic pathway traced through CaMKII/NRF2/SLC7A11; single lab","pmids":["35363929"],"is_preprint":false},{"year":2022,"finding":"CEMIP acts as an adaptor for the interaction between MHC-I and clathrin, driving MHC-I internalization via clathrin-dependent endocytosis in colorectal cancer cells. Internalized MHC-I is anchored to lysosomes for degradation, disrupting MHC-I recycling to the cell surface and reducing CD8+ T cell cytotoxicity.","method":"Co-immunoprecipitation, proximity ligation assay (CEMIP–MHC-I–clathrin), immunofluorescence (intracellular MHC-I trafficking), flow cytometry (surface MHC-I), in vivo murine CRC model, CD8+ T cell cytotoxicity assay","journal":"Journal for immunotherapy of cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP and proximity ligation define trimeric complex, trafficking defined by immunofluorescence, functional immune evasion shown in vivo; multiple orthogonal methods","pmids":["36596591"],"is_preprint":false},{"year":2022,"finding":"KIAA1199 activates TGFβ signaling by interacting with TGFBR1/2, stimulating CXCL1 and CXCL3 production, driving aggregation of immunosuppressive neutrophils that facilitate CRC liver metastasis.","method":"Co-immunoprecipitation (KIAA1199-TGFBR1/2), flow cytometry (immune cell infiltration), CXCL1/3 ELISA, siRNA knockdown, in vivo mouse CRC metastasis model","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP shows KIAA1199-TGFβR interaction, functional chemokine and immune cell readouts in vivo; single lab","pmids":["35108400"],"is_preprint":false},{"year":2022,"finding":"HIF1α lactylation (by lactate imported via MCT1) stabilizes HIF1α under normoxia. Lactylated HIF1α is a transcriptional enhancer of KIAA1199, as shown by dual-luciferase and ChIP-PCR. KIAA1199 in turn promotes angiogenesis and vasculogenic mimicry by increasing secretory VEGFA and decreasing sema3A, while elevating depolymerized HA levels; the HA biosynthesis inhibitor 4MU reversed these effects.","method":"Dual-luciferase reporter, ChIP-PCR, VEGFA ELISA, sema3A/VEGFA Western blotting, tube formation assay, 4MU treatment, in vivo tumorigenesis","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP and dual-luciferase confirm HIF1α–KIAA1199 promoter interaction; functional rescue with 4MU; single lab","pmids":["36209908"],"is_preprint":false},{"year":2023,"finding":"KIAA1199 deficiency in bone marrow stromal cells (hMSCs) enhances osteoblast differentiation and increases bone mass in vivo. Mechanistically, KIAA1199 inhibits osteopontin production by osteoblasts via integrin-mediated AKT and ERK-MAPK intracellular signaling. KIAA1199 KO mice are protected from ovariectomy-induced bone loss and show accelerated healing of bone defects.","method":"KIAA1199 knockout mice, ectopic bone formation assay, in vitro osteoblast differentiation, Western blotting (AKT, ERK-MAPK), integrin inhibition, osteopontin expression analysis, micro-CT, biomechanical testing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with multiple skeletal phenotypes, mechanistic signaling dissection via pathway inhibitors, multiple orthogonal readouts across labs/models","pmids":["37037828"],"is_preprint":false},{"year":2023,"finding":"CEMIP acts as a scaffold protein bridging MIB1 (an E3 ubiquitin ligase) and GRAF1. CEMIP interacts with the SH3 domain of GRAF1 through its 295-819aa domain and negatively regulates GRAF1 stability by facilitating MIB1-mediated ubiquitination and degradation of GRAF1. GRAF1 degradation activates CDC42/MAPK pathway-regulated EMT, promoting CRC metastasis.","method":"Co-immunoprecipitation (CEMIP-GRAF1-MIB1), domain mapping (295-819aa), ubiquitination assay, CDC42 activity assay, Western blotting, in vivo CRC metastasis model, CDC42 inhibitor","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP maps interacting domains, ubiquitination biochemically demonstrated, pharmacological and genetic rescue with CDC42 inhibitor; in vivo validation","pmids":["36849460"],"is_preprint":false},{"year":2023,"finding":"Human TMEM2 does not function as a catalytic hyaluronidase (in contrast to mouse TMEM2). In HEK293T cells, human HYBID and mouse TMEM2, but not human TMEM2, degraded extracellular HA. Chimeric domain analysis identified mouse GG domain residues His248 and Ala303 as critical for HA-degrading activity; replacing these with corresponding human TMEM2 residues (Asn248, Phe303) abolished mTMEM2 activity. In fibroblasts, hTMEM2 regulates HA metabolism by modulating HYBID and HAS2 expression.","method":"HEK293T transfection with human HYBID, mTMEM2, hTMEM2, and chimeric constructs; HA degradation assay; site-directed mutagenesis; siRNA knockdown of hTMEM2; HYBID/HAS2 expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in cells with domain-swapping mutagenesis, catalytic residue identification, loss-of-function; multiple constructs tested","pmids":["37196767"],"is_preprint":false},{"year":2023,"finding":"CEMIP inhibits c-Myc ubiquitination by hindering the interaction between FBXW7 (E3 ubiquitin ligase) and c-Myc, increasing c-Myc stabilization and nuclear accumulation, thereby promoting glutamine-dependent SCLC cell proliferation.","method":"LC-MS/MS proteomics, co-immunoprecipitation (CEMIP-FBXW7-c-Myc), ubiquitination assay, c-Myc nuclear fractionation, GLS1 inhibitor CB-839, in vivo/in vitro functional assays","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and ubiquitination assay define mechanism; pharmacological inhibitor used for functional validation; single lab","pmids":["36746261"],"is_preprint":false},{"year":2024,"finding":"ALKBH5 (m6A demethylase) negatively regulates CEMIP expression by reducing the stability of CEMIP mRNA. Reduced ALKBH5 in paclitaxel-resistant NSCLC cells leads to elevated CEMIP, promoting EMT and drug resistance; ALKBH5 overexpression reverses EMT and restores paclitaxel sensitivity.","method":"RNA-seq, RT-PCR, Western blotting, mRNA stability assay, ALKBH5 overexpression/knockdown, paclitaxel sensitivity assay, EMT marker analysis","journal":"Toxicology and applied pharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mRNA stability assay links m6A modification to CEMIP regulation; functional EMT and drug resistance phenotypes; single lab","pmids":["38199493"],"is_preprint":false},{"year":2003,"finding":"A point mutation H783Y in KIAA1199 causes an unusual cytoplasmic distribution pattern distinct from the localization of wild-type protein, suggesting altered subcellular trafficking as a potential mechanism of hearing impairment.","method":"Site-directed mutagenesis, in vitro subcellular localization by microscopy","journal":"Journal of human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization experiment with single mutant; no functional pathway mechanistic detail; single lab","pmids":["14577002"],"is_preprint":false}],"current_model":"CEMIP (KIAA1199/HYBID) is a multifunctional protein that primarily mediates clathrin-dependent, CD44/HYAL-independent hyaluronan depolymerization through binding and intracellular trafficking of HA; it localizes to the endoplasmic reticulum (where it complexes with BiP and ITPR3 to modulate calcium signaling and promote PKCα-driven cell migration), to endosomes (where it scaffolds MEK1 to sustain ERK1/2 signaling), and to the cell surface (where its G8 domain binds ANXA1 to enable extracellular HA degradation); it acts as a scaffold for OGT/β-catenin O-GlcNAcylation, for MIB1/GRAF1 ubiquitin-mediated CDC42/MAPK activation, and for FBXW7/c-Myc stabilization; it drives anoikis resistance via ATF4-triggered PKCα phosphorylation of Bcl-2/Beclin1 autophagy and ITPR3/CaMKII/NRF2/SLC7A11-mediated ferroptosis resistance; it is transcriptionally regulated by NF-κB (via BCL-3/p65), HIF-2α, HIF1α lactylation, and ALKBH5-mediated m6A mRNA stability; in the tumor microenvironment, exosomal CEMIP conditions the brain pre-metastatic niche through endothelial branching and inflammation, drives immune evasion by acting as a clathrin adaptor for MHC-I internalization and lysosomal degradation, and promotes immunosuppressive neutrophil infiltration via TGFβR1/2-CXCL1/3 signaling; in normal physiology, it is required for HA homeostasis in skin, synovium, cartilage, cochlea, and brain, where its loss impairs hippocampal memory and dendritic spine density."},"narrative":{"mechanistic_narrative":"CEMIP (KIAA1199/HYBID) is the principal effector of CD44- and HYAL-independent hyaluronan (HA) depolymerization, binding HA directly and catabolizing it through an endo-β-N-acetylglucosaminidase-dependent clathrin-coated pit pathway in fibroblasts and tumor cells [PMID:23509262]. Proper HA-degrading activity depends on intracellular trafficking governed by an N-terminal cleavable signal sequence and an ER-retention motif: in the ER, CEMIP complexes with the chaperone BiP and the calcium channel ITPR3, driving ER calcium leakage that activates PKCα to promote cell migration [PMID:23990668, PMID:23936024]. At the cell surface its G8 domain binds ANXA1 to anchor secreted CEMIP for extracellular HA degradation [PMID:33473125], while in endosomes it scaffolds MEK1 to sustain ERK1/2 signaling [PMID:29915160]. CEMIP transcription is tightly controlled by inflammatory and hypoxic inputs, including NF-κB downstream of IL-6/IL-1β [PMID:27981209, PMID:33473125], HIF-2α and lactylated HIF1α [PMID:26009875, PMID:36209908], with TGF-β1 suppressing it via PI3K-Akt to govern the molecular weight of newly synthesized HA [PMID:26518873], and ALKBH5-mediated m6A demethylation destabilizing its mRNA [PMID:38199493]. Beyond HA turnover, CEMIP functions as a versatile scaffold/adaptor coupling receptor and metabolic signaling: it potentiates EGFR-dependent Src/MEK/ERK signaling and EMT [PMID:25366117], bridges OGT and β-catenin to enhance β-catenin O-GlcNAcylation and glutamine-metabolic reprogramming [PMID:34608265], links MIB1 to GRAF1 for ubiquitin-mediated GRAF1 degradation and CDC42/MAPK-driven EMT [PMID:36849460], binds PP2A to dephosphorylate stathmin and destabilize microtubules [PMID:30202098], and acts as a clathrin adaptor for MHC-I internalization and lysosomal degradation to drive immune evasion [PMID:36596591]. In cancer it confers anoikis, hypoxia, and ferroptosis resistance through ATF4/PKCα/Bcl-2/Beclin1 autophagy and ITPR3/CaMKII/NRF2/SLC7A11 axes [PMID:35013120, PMID:35363929], and exosomal CEMIP conditions the brain pre-metastatic niche via endothelial branching and perivascular inflammation [PMID:31685984]. Physiologically, CEMIP is required for HA homeostasis in skin, synovium, brain, and bone, where its loss alters antimicrobial defense, dendritic spine density, arthritis susceptibility, and bone mass [PMID:31914398, PMID:30060951, PMID:33473125, PMID:37037828].","teleology":[{"year":2013,"claim":"Established CEMIP's core molecular identity by showing it mediates HA depolymerization independently of the canonical CD44/HYAL system, resolving the question of how cells catabolize HA through an unexpected clathrin-coated pit route.","evidence":"Glycosaminoglycan-binding assays, siRNA knockdown, cDNA transfection, and clathrin pathway inhibition in skin fibroblasts and disease specimens","pmids":["23509262"],"confidence":"High","gaps":["Catalytic mechanism and whether CEMIP itself or an associated enzyme cleaves HA not fully resolved","No structural model of the HA-binding/catalytic site"]},{"year":2013,"claim":"Defined the subcellular basis of CEMIP function, showing ER localization, BiP complex formation, and ER-retention-motif-dependent calcium leakage couple CEMIP to PKCα-driven migration, and that trafficking-determining sequences are required for HA depolymerization.","evidence":"SNAP-tag pull-down, FRET calcium measurement, mutagenesis of ER-retention/signal motifs, confocal imaging, and xenografts","pmids":["23990668","24269685","23936024"],"confidence":"High","gaps":["How a single protein partitions between ER, surface, and secreted pools is unclear","Interaction with ITPR3 from a single proteomics/Co-IP study"]},{"year":2014,"claim":"Extended CEMIP beyond HA biology into receptor signaling, identifying it as an NF-κB (BCL-3/p65) target that binds EGFR and Plexin A2 to sustain Src/MEK/ERK signaling, EGF-driven EMT, and protection from Semaphorin 3A death.","evidence":"ChIP, reciprocal Co-IP, siRNA/overexpression, and cell death assays","pmids":["25366117"],"confidence":"High","gaps":["Whether EGFR binding is direct vs. complex-mediated not established","Link between HA-degrading activity and receptor scaffolding undefined"]},{"year":2015,"claim":"Resolved the hypoxic transcriptional control of CEMIP by showing HIF-2α (not HIF-1α) binds the CEMIP promoter and that Jarid1A-dependent H3K4me3 changes gate expression, positioning CEMIP as a hypoxia-driven migration effector.","evidence":"ChIP, isoform-specific knockdown, H3K4me3 chromatin analysis, and migration assays","pmids":["26009875"],"confidence":"High","gaps":["Reconciliation with later HIF1α-lactylation regulation not addressed","Context dependence of HIF isoform usage unknown"]},{"year":2015,"claim":"Connected CEMIP to growth-factor and cytokine control of HA size, showing TGF-β1 suppresses HYBID via PI3K-Akt while inducing HAS, determining whether high- or low-MW HA accumulates in normal vs. arthritic synovium.","evidence":"siRNA, pathway-specific inhibitors, HA size-exclusion chromatography, and clinical tissue correlation","pmids":["26518873","27981209","28179576"],"confidence":"High","gaps":["Direct transcription factors downstream of these pathways at the CEMIP locus not fully mapped"]},{"year":2017,"claim":"Identified CEMIP as a signaling hub in normal cell physiology, controlling Nrg1/MEK/ERK-driven Schwann cell dedifferentiation and myelin clearance, and binding WBP11/PTP4A3 to gate FGFR4/Wnt and EGFR signaling.","evidence":"RNAi, conditional Cre-lox knockout mice, Nrg1 stimulation, Co-IP, and rescue assays","pmids":["28699206","30626935"],"confidence":"High","gaps":["Mechanism by which CEMIP positions MEK1/ERK in Schwann cells vs. tumor endosomes not unified","WBP11/PTP4A3 interactions from a single lab"]},{"year":2018,"claim":"Defined endosomal scaffolding of MEK1 as the basis for CEMIP-driven MEK-inhibitor resistance, and revealed multiple scaffold functions (PP2A/stathmin/microtubule destabilization; BiP-promoter-driven hypoxia adaptation) underlying motility and survival.","evidence":"Endosomal fractionation, Co-IP, organoids, in vivo models, phosphatase/microtubule assays, and promoter reporters","pmids":["29915160","30202098","29505302","31303964"],"confidence":"High","gaps":["How CEMIP simultaneously engages PP2A, MEK1, and metabolic programs not integrated","Several functional links rest on single-lab data"]},{"year":2018,"claim":"Demonstrated that CEMIP, not the related TMEM2, is the indispensable HA depolymerase in human fibroblasts, with TMEM2 acting only as an expression modulator, clarifying the division of labor in HA catabolism.","evidence":"Separate siRNA knockdowns, HA depolymerization assays across cell lines","pmids":["30241936"],"confidence":"Medium","gaps":["Functional knockdown without reconstitution","Catalytic vs. trafficking contribution of CEMIP not separated"]},{"year":2019,"claim":"Established physiological and microenvironmental roles, showing exosomal CEMIP conditions the brain pre-metastatic niche, and CEMIP drives β-catenin-dependent chondrocyte transdifferentiation, hMSC migration, and metabolic reprogramming.","evidence":"Exosome proteomics with depletion/rescue, RNA-seq, shRNA/CRISPR, signaling rescue, and in vivo metastasis models","pmids":["31685984","30718510","30755597","29505302"],"confidence":"High","gaps":["Mechanism of CEMIP exosomal loading and uptake unknown","How extracellular CEMIP acts on recipient cells not defined"]},{"year":2020,"claim":"Used knockout mice to define normal physiological requirements for CEMIP-mediated HA turnover in skin antimicrobial defense and brain synaptic structure, and dissected histamine-driven CEMIP induction in skin.","evidence":"Cemip knockout mice with S. aureus challenge, Golgi-Cox/doublecortin staining, and pharmacological H1-receptor/PKCδ/PI3K dissection","pmids":["31914398","30060951","31949043"],"confidence":"High","gaps":["Brain phenotype from a single lab without independent replication","Causal link between HA accumulation and synaptic deficits incomplete"]},{"year":2021,"claim":"Mapped the extracellular HA-degradation machinery to a G8-domain/ANXA1 membrane-tethering mechanism required in vivo for arthritis pathology, and identified CEMIP as an OGT adaptor enabling β-catenin O-GlcNAcylation and glutamine reprogramming.","evidence":"G8-deleted vs. full-length rescue in knockout mice with collagen-induced arthritis; Co-IP of CEMIP-OGT-β-catenin with O-GlcNAcylation assays and metastasis models","pmids":["33473125","34608265"],"confidence":"High","gaps":["Structural basis of G8/ANXA1 binding not resolved","Whether OGT scaffolding and HA degradation are coupled unknown"]},{"year":2022,"claim":"Defined CEMIP-driven stress-resistance and immune-evasion mechanisms in cancer: ATF4/PKCα/Bcl-2/Beclin1 autophagy for anoikis resistance, ITPR3/CaMKII/NRF2/SLC7A11 for ferroptosis resistance, clathrin-adaptor-mediated MHC-I degradation, TGFβR-CXCL1/3 neutrophil recruitment, and HIF1α-lactylation-driven angiogenesis.","evidence":"Co-IP, proximity ligation, flow cytometry, CD8+ T-cell cytotoxicity, ChIP/dual-luciferase, and in vivo metastasis models","pmids":["35013120","35363929","36596591","35108400","36209908"],"confidence":"High","gaps":["Most stress-resistance chains validated in single labs","How one scaffold mediates such divergent adaptor functions unresolved"]},{"year":2023,"claim":"Established CEMIP as a regulator of ubiquitin-ligase activity—bridging MIB1 to GRAF1 for degradation and blocking FBXW7-mediated c-Myc turnover—and defined skeletal physiology where CEMIP loss increases osteoblast differentiation and bone mass; human TMEM2 was shown to be catalytically inactive unlike mouse.","evidence":"Domain-mapped Co-IP, ubiquitination assays, CDC42/integrin signaling dissection, knockout mice with micro-CT, and HEK293T reconstitution with domain-swap mutagenesis","pmids":["36849460","36746261","37037828","37196767"],"confidence":"High","gaps":["Structural mechanism of scaffold-directed ubiquitination unknown","Whether CEMIP's catalytic HA mechanism parallels the TMEM2 GG-domain chemistry untested"]},{"year":2024,"claim":"Added post-transcriptional control by showing ALKBH5-mediated m6A demethylation destabilizes CEMIP mRNA, linking loss of this regulation to EMT and paclitaxel resistance.","evidence":"mRNA stability assays, ALKBH5 overexpression/knockdown, and drug-sensitivity/EMT marker analysis in NSCLC","pmids":["38199493"],"confidence":"Medium","gaps":["m6A sites on CEMIP mRNA not mapped","Single-lab finding without independent replication"]},{"year":null,"claim":"The unifying biochemical question—how CEMIP's intrinsic HA-depolymerizing activity mechanistically relates to its many protein-scaffold/adaptor functions, and what structural features partition it among ER, endosome, surface, and secreted pools—remains open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of CEMIP or its catalytic/HA-binding site","No reconstituted enzymatic assay distinguishing direct catalysis from adaptor recruitment","Mechanism partitioning CEMIP across compartments undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[13,25,28,32]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,34]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,24]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,9,24]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[14,25,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,13,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,24,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[28,29]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,8,16]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,28]}],"complexes":[],"partners":["BIP","ITPR3","EGFR","OGT","CTNNB1","MEK1","PP2A","MIB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WUJ3","full_name":"Cell migration-inducing and hyaluronan-binding protein","aliases":["Hyaluronan binding protein involved in hyaluronan depolymerization"],"length_aa":1361,"mass_kda":153.0,"function":"Mediates depolymerization of hyaluronic acid (HA) via the cell membrane-associated clathrin-coated pit endocytic pathway. Binds to hyaluronic acid. Hydrolyzes high molecular weight hyaluronic acid to produce an intermediate-sized product, a process that may occur through rapid vesicle endocytosis and recycling without intracytoplasmic accumulation or digestion in lysosomes. Involved in hyaluronan catabolism in the dermis of the skin and arthritic synovium. Positively regulates epithelial-mesenchymal transition (EMT), and hence tumor cell growth, invasion and cancer dissemination. In collaboration with HSPA5/BIP, promotes cancer cell migration in a calcium and PKC-dependent manner. May be involved in hearing","subcellular_location":"Nucleus; Cytoplasm; Endoplasmic reticulum; Cell membrane; Membrane, clathrin-coated pit; Secreted","url":"https://www.uniprot.org/uniprotkb/Q8WUJ3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CEMIP","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":[],"url":"https://opencell.sf.czbiohub.org/search/CEMIP","total_profiled":1310},"omim":[{"mim_id":"612033","title":"PAXIP1-ASSOCIATED GLUTAMATE-RICH PROTEIN 1; PAGR1","url":"https://www.omim.org/entry/612033"},{"mim_id":"608366","title":"CELL MIGRATION-INDUCING HYALURONIDASE 1; CEMIP","url":"https://www.omim.org/entry/608366"},{"mim_id":"605835","title":"CELL MIGRATION-INDUCING HYALURONIDASE 2; CEMIP2","url":"https://www.omim.org/entry/605835"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli fibrillar center","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Additional"},{"location":"Endoplasmic reticulum","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"endometrium 1","ntpm":30.0}],"url":"https://www.proteinatlas.org/search/CEMIP"},"hgnc":{"alias_symbol":["IR2155535","TMEM2L","HYBID","CEMIP1"],"prev_symbol":["KIAA1199"]},"alphafold":{"accession":"Q8WUJ3","domains":[{"cath_id":"-","chopping":"178-322","consensus_level":"high","plddt":90.8509,"start":178,"end":322},{"cath_id":"-","chopping":"324-405","consensus_level":"high","plddt":71.261,"start":324,"end":405},{"cath_id":"-","chopping":"421-480","consensus_level":"high","plddt":94.929,"start":421,"end":480},{"cath_id":"-","chopping":"788-999_1192-1204","consensus_level":"medium","plddt":92.1622,"start":788,"end":1204},{"cath_id":"-","chopping":"1210-1354","consensus_level":"high","plddt":90.1519,"start":1210,"end":1354},{"cath_id":"2.60.40","chopping":"1001-1182","consensus_level":"high","plddt":92.1849,"start":1001,"end":1182}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUJ3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUJ3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUJ3-F1-predicted_aligned_error_v6.png","plddt_mean":90.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CEMIP","jax_strain_url":"https://www.jax.org/strain/search?query=CEMIP"},"sequence":{"accession":"Q8WUJ3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WUJ3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WUJ3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUJ3"}},"corpus_meta":[{"pmid":"31685984","id":"PMC_31685984","title":"Tumour 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Specific HA binding was demonstrated in glycosaminoglycan-binding assays; knockdown abolished HA degradation by skin fibroblasts; transfection of KIAA1199 cDNA conferred HA catabolism via an endo-β-N-acetylglucosaminidase-dependent mechanism through the clathrin-coated pit pathway.\",\n      \"method\": \"Glycosaminoglycan-binding assay, siRNA knockdown, cDNA transfection, clathrin pathway inhibition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro assays (binding assay, KD, gain-of-function), mechanistic pathway defined, replicated in multiple cell types including disease specimens\",\n      \"pmids\": [\"23509262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KIAA1199 localizes to the endoplasmic reticulum where it forms a stable complex with the chaperone BiP. An ER-retention motif within KIAA1199 is required for ER localization, BiP interaction, and enhanced cell migration. KIAA1199 mediates ER calcium leakage, and the resultant increase in cytosolic calcium activates protein kinase C alpha (PKCα), promoting cell migration.\",\n      \"method\": \"SNAP-tag pull-down assay, confocal microscopy, FRET-based calcium measurement, spectrofluorometry, Western blotting, mutagenesis of ER-retention motif, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (pulldown, FRET, mutagenesis, imaging), both loss-of-function and gain-of-function with defined molecular mechanism\",\n      \"pmids\": [\"23990668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The N-terminal 30 amino acids of KIAA1199 function as a cleavable signal sequence required for proper intracellular trafficking and KIAA1199-mediated HA depolymerization. Deletion of the N-terminal portion results in altered intracellular trafficking and loss of HA depolymerization activity.\",\n      \"method\": \"N-terminal deletion constructs, intracellular trafficking assays, HA depolymerization assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — functional mutagenesis combined with trafficking and enzymatic assays, single lab\",\n      \"pmids\": [\"24269685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KIAA1199 is secreted into the extracellular environment by colon cancer cells. It is found in the perinuclear ER and at the cell membrane. Co-immunoprecipitation confirmed interaction with the cell membrane receptor ephrin A2 and with the ER receptor ITPR3 (a key Ca2+ signaling component), linking KIAA1199 to Ca2+ and Wnt/CTNNB1 signaling.\",\n      \"method\": \"Immunostaining, mass spectrometry proteomics, co-immunoprecipitation, transcriptomics\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP confirmed specific interactions with EphA2 and ITPR3, supported by proteomics; single lab\",\n      \"pmids\": [\"23936024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Murine Kiaa1199 (mKiaa1199) binds hyaluronan specifically and mediates HA depolymerization via the clathrin-coated pit pathway, consistent with the human ortholog, though slight differences exist in minimum HA degradate sizes.\",\n      \"method\": \"cDNA transfection in cells, glycosaminoglycan-binding assay, HA catabolism assay, clathrin pathway inhibition\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional replication in murine ortholog using same experimental framework as human studies; single lab\",\n      \"pmids\": [\"24251095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIAA1199 is a BCL-3- and p65-dependent NF-κB target gene. It binds Plexin A2 and protects cells from Semaphorin 3A-mediated cell death by promoting EGFR stability and signaling. KIAA1199 is an EGFR-binding protein and its deficiency impairs EGF-dependent Src, MEK1, and ERK1/2 phosphorylations, thereby promoting EGF-mediated EMT.\",\n      \"method\": \"ChIP, co-immunoprecipitation, Western blotting, siRNA knockdown, overexpression, cell death assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction studies (Co-IP for EGFR and PlexinA2 binding), ChIP for transcriptional regulation, multiple orthogonal functional readouts\",\n      \"pmids\": [\"25366117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIAA1199 interacts with glycogen phosphorylase kinase β-subunit (PHKB) via its C-terminal region, as demonstrated by pull-down assay. Under serum-free conditions, KIAA1199 also interacts with glycogen phosphorylase brain form (PYGB). These interactions promote glycogen breakdown and cancer cell survival.\",\n      \"method\": \"MBP fusion protein pull-down assay, retroviral overexpression, glycogen breakdown assays, cell survival assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pull-down with defined C-terminal domain plus functional glycogen assay; single lab, no reciprocal Co-IP\",\n      \"pmids\": [\"25051373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HIF-2α (but not HIF-1α) directly binds to the hypoxia response element within the CEMIP promoter, driving CEMIP transcription under hypoxic conditions. CEMIP is a downstream effector of HIF-2α-mediated cell migration. CEMIP expression negatively correlates with histone demethylase Jarid1A; low oxygen inhibits Jarid1A, increasing H3K4me3 at the CEMIP promoter.\",\n      \"method\": \"ChIP, promoter binding assay, siRNA knockdown of HIF-1α vs HIF-2α, H3K4me3 chromatin analysis, cell migration assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct promoter binding shown by ChIP, isoform-specific knockdown discriminating HIF-1α vs HIF-2α, multiple orthogonal methods\",\n      \"pmids\": [\"26009875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TGF-β1, bFGF, EGF, and PDGF-BB commonly enhance total HA in skin fibroblasts through HAS up-regulation, but molecular size of newly produced HA depends on HYBID/KIAA1199 expression. TGF-β1 suppresses HYBID expression via PI3K-Akt signaling and stimulates HAS1/2 via MAPK/Smad, resulting in high molecular weight HA. In arthritic synovial fibroblasts, inefficient TGF-β1-mediated suppression of HYBID leads to accumulation of low-MW HA.\",\n      \"method\": \"siRNA knockdown, signaling pathway inhibitors (PI3K, MAPK, Smad), HA size-exclusion chromatography, gene expression analysis, human tissue correlation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection of signaling pathways with specific inhibitors, validated in multiple cell types and clinical specimens\",\n      \"pmids\": [\"26518873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crohn's Disease fibroblasts overproduce KIAA1199 primarily through an IL-6-driven autocrine mechanism. IL-6 stimulation increases KIAA1199 deposition in the ECM. siRNA silencing of KIAA1199 abrogated HA degradation by colon fibroblasts. Antibody blockade of IL-6 receptors decreased KIAA1199 protein in the ECM.\",\n      \"method\": \"siRNA knockdown, IL-6 receptor antibody blockade, HA degradation biochemical assay, immunoblot, immunostaining of clinical specimens\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA, antibody blockade, biochemical HA assay), patient specimens, clear mechanistic link\",\n      \"pmids\": [\"27981209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KIAA1199 expression in cancer cells is induced by pro-inflammatory cytokine IL-1β and suppressed by the COX-2 inhibitor NS-398. Forced expression of KIAA1199 increases low-molecular-weight HA in conditioned medium. siRNA knockdown decreases cell migration and proliferation in pancreatic cancer.\",\n      \"method\": \"siRNA knockdown, gene transduction (overexpression), IL-1β stimulation, NS-398 treatment, HA molecular weight analysis of conditioned medium\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — gain- and loss-of-function with defined cytokine regulation; single lab; HA size analysis links KIAA1199 to LMW-HA production\",\n      \"pmids\": [\"28179576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KIAA1199 interacts with WBP11 (WW domain binding protein 11) and PTP4A3 (protein tyrosine phosphatase type IVA, member 3). This binding activates FGFR4/Wnt/β-catenin and EGFR signaling pathways to regulate E-cadherin and N-cadherin expression. Ectopic expression of WBP11 or PTP4A3 blocked KIAA1199-stimulated cell proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, Western blotting, in vitro and in vivo functional assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP identifies binding partners, functional rescue experiments; single lab\",\n      \"pmids\": [\"30626935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KIAA1199 promotes Nrg1-dependent MEK1 and ERK1/2 activation in Schwann cells. In the absence of KIAA1199, SC dedifferentiation is impaired: cJun and negative regulators of myelination are decreased while Krox20 is elevated, driving a pro-myelinating phenotype. KIAA1199-deficient SCs show lower myelin clearance and increased myelination capacity.\",\n      \"method\": \"RNA interference, conditional Cre-lox knockout mice (tamoxifen-inducible), Nrg1 stimulation, Western blotting for MEK/ERK pathway components, myelination assays\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — both RNAi and conditional in vivo knockout with multiple molecular and cellular readouts; defines pathway position in MEK/ERK signaling in Schwann cells\",\n      \"pmids\": [\"28699206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CEMIP localizes to endosomes where it acts as a scaffold protein binding MEK1, sustaining ERK1/2 activation in BRAF-mutated MEK1-inhibitor-resistant colorectal cancers. CEMIP expression is induced by β-catenin- and FRA-1-dependent Wnt pathway activation. CEMIP-dependent ERK1/2 signaling maintains c-Myc protein levels, providing metabolic advantage to resistant cells.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation (CEMIP–MEK1 interaction), endosomal fractionation, Western blotting, intestinal organoids, in vivo mouse models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endosomal localization plus Co-IP of MEK1, functional epistasis in organoids and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"29915160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The AMPK/GSK3β/β-catenin cascade drives CEMIP overexpression in anoikis-resistant prostate cancer cells. CEMIP promotes migration, invasion, and metabolic reprogramming via PDK4 upregulation, increasing pyruvate and lactate production. CRISPR knockout of CEMIP reversed these effects and reduced MMP2, VEGF, PDK4, and lactate dehydrogenase A expression.\",\n      \"method\": \"CRISPR/Cas9 knockout, Western blotting, metabolic assays (pyruvate, lactate, ATP), genome microarray, migration/invasion assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with metabolic and functional readouts, pathway defined; single lab\",\n      \"pmids\": [\"29505302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KIAA1199 interacts with protein phosphatase 2A (PP2A) through its C-terminal domain and increases PP2A phosphatase activity. Downstream, stathmin (a microtubule-destabilizing protein) is dephosphorylated, leading to microtubule destabilization and enhanced cell motility. Paclitaxel (microtubule-stabilizing drug) prevents KIAA1199-induced microtubule destabilization.\",\n      \"method\": \"Co-immunoprecipitation (KIAA1199-PP2A), phosphatase activity assays, stathmin phosphorylation Western blotting, microtubule polymerization assays, paclitaxel rescue, in vivo orthotopic model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, enzymatic activity assay, pharmacological rescue with paclitaxel, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"30202098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HYBID/KIAA1199 is indispensable for HA depolymerization in skin fibroblasts; TMEM2 knockdown unexpectedly enhanced HA depolymerization rather than reducing it, demonstrating that TMEM2 is not involved as a catalytic hyaluronidase in HYBID-mediated HA depolymerization. TGF-β1 coordinately suppresses HYBID expression and upregulates TMEM2 expression.\",\n      \"method\": \"siRNA knockdown of HYBID and TMEM2 separately, HA depolymerization assay, TGF-β1 and growth factor treatment, multiple cell lines\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional siRNA knockdown with biochemical HA assay, multiple cell types; single lab\",\n      \"pmids\": [\"30241936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CEMIP upregulates BiP transcript and protein levels by mediating activation of the BiP promoter in breast cancer cells. CEMIP overexpression confers protective adaptations to hypoxia (decreased apoptosis, activated autophagy, increased glucose uptake). BiP signals downstream of CEMIP to modulate cellular resistance to hypoxia; reducing BiP in CEMIP-expressing cells sensitized cells to hypoxia and caused tumor regression in vivo.\",\n      \"method\": \"BiP promoter reporter assay, siRNA knockdown, overexpression, hypoxia treatment, apoptosis/autophagy assays, glucose uptake assay, in vivo xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — promoter assay plus functional epistasis (BiP knockdown in CEMIP-expressing cells) with in vivo validation; single lab\",\n      \"pmids\": [\"31303964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CEMIP protein is elevated in exosomes from brain metastatic cancer cells. Uptake of CEMIP+ exosomes by brain endothelial and microglial cells induces endothelial cell branching and inflammation in the perivascular niche, upregulating pro-inflammatory cytokines (Ptgs2, Tnf, Ccl/Cxcl) that promote brain vascular remodeling. CEMIP depletion in tumor cells impaired brain metastasis and tumor-vasculature association, phenotypes rescued by pre-conditioning the brain with CEMIP+ exosomes.\",\n      \"method\": \"Proteomic analysis of exosomes, CEMIP depletion (genetic), exosome uptake experiments, brain endothelial/microglial co-culture, cytokine profiling, in vivo brain metastasis model with exosome pre-conditioning\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — exosome proteomics, genetic depletion with rescue by exosome pre-conditioning, in vivo validation, multiple cell type targets and cytokine readouts\",\n      \"pmids\": [\"31685984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CEMIP promotes fibrosis-like transdifferentiation of OA chondrocytes into 'chondro-myo-fibroblasts' expressing α-SMA and type III collagen. CEMIP regulates β-catenin protein level, is required for chondrocyte proliferation, and promotes TGFβ signaling via the p-Smad2/3 (Alk5/PAI-1) pathway. CEMIP expression is induced by the pSmad1/5 (Alk1) pathway.\",\n      \"method\": \"siRNA knockdown, high-throughput RNA sequencing, Western blotting, in vitro chondrocyte dedifferentiation model, human and mouse OA tissue analysis, in situ co-localization\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RNA-seq and functional assays identify TGFβ pathway connections; pathway assignment via siRNA; single lab\",\n      \"pmids\": [\"30718510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KIAA1199 promotes osteoblastic stem cell (hMSC) migration. KIAA1199-deficient hMSCs show changes in cell morphology, reduced F-actin polymerization, and altered phosphorylation of cofilin1 (CFL1) and LIM-domain kinase 1 (LIMK1). KIAA1199 activates P38 kinase and its associated changes in Wnt signaling; impaired Wnt/TCF reporter activity in KIAA1199-deficient hMSCs was rescued by KIAA1199 treatment.\",\n      \"method\": \"shRNA knockdown, scratch assay, trans-well migration, F-actin staining, Western blotting (pCFL1, pLIMK1, DSTN), TCF-reporter assay, P38 kinase assay, rescue with recombinant KIAA1199\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple molecular readouts plus signaling rescue; single lab, no independent replication\",\n      \"pmids\": [\"30755597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cemip is the major inducible gene responsible for hyaluronan catabolism in mouse dermis upon S. aureus infection. Cemip-/- mice failed to digest hyaluronan and had significantly less infection after intradermal S. aureus challenge. Stabilization of large-MW HA in Cemip-/- mice enabled increased cathelicidin antimicrobial peptide (Camp) expression, partly through enhanced differentiation of preadipocytes to adipocytes. Cemip-/- mice also showed greater IL-6 expression and neutrophil infiltration.\",\n      \"method\": \"Cemip knockout mice (genetic), intradermal S. aureus challenge, HA molecular weight analysis, Camp/antimicrobial peptide expression, histology (Pref1, PPARγ, Adipoq markers), IL-6 and neutrophil quantification\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout model with infectious challenge, multiple mechanistic readouts linking HA degradation to adipocyte differentiation and antimicrobial defense; orthogonal methods\",\n      \"pmids\": [\"31914398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HYBID/KIAA1199 knockout mice show decreased dendritic spine density in the dentate gyrus granule cells, accompanied by HA accumulation and decreased doublecortin-positive immature neurons in the dentate gyrus, suggesting HYBID-mediated HA degradation is critical for synaptic formation and cognitive function.\",\n      \"method\": \"Hybid knockout mice, Golgi-Cox staining (dendritic spine density), HA staining, doublecortin immunostaining\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with cellular and molecular phenotypes; single lab, no independent replication\",\n      \"pmids\": [\"30060951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Histamine increases HA degradation in skin fibroblasts by up-regulating HYBID/KIAA1199 and down-regulating HAS2. The histamine H1 receptor mediates these effects. HYBID up-regulation requires protein kinase Cδ signaling, while HAS2 suppression requires PI3K-Akt signaling downstream of H1 receptor.\",\n      \"method\": \"Histamine H1 agonist/antagonist, PKCδ inhibitor, PI3K-Akt inhibitor, HA molecular weight analysis, HYBID/HAS2 expression analysis, immunohistochemistry in human skin biopsies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological dissection of separate signaling pathways with specific inhibitors, validated in human tissue; multiple orthogonal methods\",\n      \"pmids\": [\"31949043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Secreted KIAA1199 mediates extracellular HA degradation by attaching to the cell membrane of RA fibroblast-like synoviocytes via its G8 domain binding to ANXA1. In vivo, KIAA1199 knockout mice showed greater resistance to collagen-induced arthritis, partially reversed by intra-articular injection of full-length but not G8-deleted KIAA1199. NF-κB activation by IL-6 through PI3K/Akt signaling is the main pathway inducing KIAA1199 expression in RA FLS.\",\n      \"method\": \"Anti-KIAA1199 mAb treatment, KIAA1199 KO mice, collagen-induced arthritis model, intra-articular gene injection (WT vs G8-deleted mutant), cell membrane binding assay, HA degradation assay, NF-κB/PI3K/Akt inhibitor analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-specific mutant rescue experiment defines G8/ANXA1 interaction as mechanistically required; in vivo KO with rescue, multiple orthogonal methods\",\n      \"pmids\": [\"33473125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CEMIP acts as a novel adaptor protein for O-GlcNAc transferase (OGT). CEMIP interacts with OGT and β-catenin, leading to elevated O-GlcNAcylation of β-catenin and enhanced β-catenin nuclear translocation. Nuclear β-catenin then enhances CEMIP transcription in a reciprocal positive feedback loop and upregulates glutaminase 1, SLC1A5, and SLC38A2 (glutamine transporters) to promote glutamine metabolic reprogramming and CRC metastasis.\",\n      \"method\": \"Co-immunoprecipitation (CEMIP-OGT-β-catenin complex), O-GlcNAcylation assay, β-catenin nuclear fractionation, transcriptional reporter, in vivo CRC metastasis model with combinational inhibition\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP defines trimeric complex, O-GlcNAcylation biochemically demonstrated, reciprocal regulation validated with in vivo readout; multiple orthogonal methods\",\n      \"pmids\": [\"34608265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATF4 triggers CEMIP transcription during ECM detachment, and elevated CEMIP promotes PKCα membrane translocation, leading to serine-70 phosphorylation of Bcl-2. This phosphorylation dissociates the Bcl-2/Beclin1 complex, inducing protective autophagy and anoikis resistance in prostate cancer cells.\",\n      \"method\": \"siRNA knockdown, Western blotting (pBcl-2 Ser70, Beclin1 complex), PKCα translocation assay, autophagy flux assay, ATF4 ChIP/promoter analysis, in vivo metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mechanistic chain defined (ATF4→CEMIP→PKCα→pBcl-2→Beclin1 dissociation→autophagy), multiple Western readouts; single lab\",\n      \"pmids\": [\"35013120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CEMIP promotes ferroptosis resistance during ECM detachment by promoting cystine uptake. Mechanistically, CEMIP interacts with ITPR3 to modulate ER calcium leakage, activating CaMKII, which phosphorylates NRF2 and promotes its nuclear localization, leading to elevated SLC7A11 transcription (a cystine/glutamate antiporter). Silencing CEMIP abolishes cystine uptake promotion and ferroptosis resistance.\",\n      \"method\": \"Co-immunoprecipitation (CEMIP-ITPR3), CaMKII activity assay, NRF2 nuclear fractionation, SLC7A11 expression analysis, cystine uptake assay, ferroptosis assays, siRNA knockdown\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP identifies CEMIP-ITPR3 interaction, mechanistic pathway traced through CaMKII/NRF2/SLC7A11; single lab\",\n      \"pmids\": [\"35363929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CEMIP acts as an adaptor for the interaction between MHC-I and clathrin, driving MHC-I internalization via clathrin-dependent endocytosis in colorectal cancer cells. Internalized MHC-I is anchored to lysosomes for degradation, disrupting MHC-I recycling to the cell surface and reducing CD8+ T cell cytotoxicity.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay (CEMIP–MHC-I–clathrin), immunofluorescence (intracellular MHC-I trafficking), flow cytometry (surface MHC-I), in vivo murine CRC model, CD8+ T cell cytotoxicity assay\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP and proximity ligation define trimeric complex, trafficking defined by immunofluorescence, functional immune evasion shown in vivo; multiple orthogonal methods\",\n      \"pmids\": [\"36596591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIAA1199 activates TGFβ signaling by interacting with TGFBR1/2, stimulating CXCL1 and CXCL3 production, driving aggregation of immunosuppressive neutrophils that facilitate CRC liver metastasis.\",\n      \"method\": \"Co-immunoprecipitation (KIAA1199-TGFBR1/2), flow cytometry (immune cell infiltration), CXCL1/3 ELISA, siRNA knockdown, in vivo mouse CRC metastasis model\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP shows KIAA1199-TGFβR interaction, functional chemokine and immune cell readouts in vivo; single lab\",\n      \"pmids\": [\"35108400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HIF1α lactylation (by lactate imported via MCT1) stabilizes HIF1α under normoxia. Lactylated HIF1α is a transcriptional enhancer of KIAA1199, as shown by dual-luciferase and ChIP-PCR. KIAA1199 in turn promotes angiogenesis and vasculogenic mimicry by increasing secretory VEGFA and decreasing sema3A, while elevating depolymerized HA levels; the HA biosynthesis inhibitor 4MU reversed these effects.\",\n      \"method\": \"Dual-luciferase reporter, ChIP-PCR, VEGFA ELISA, sema3A/VEGFA Western blotting, tube formation assay, 4MU treatment, in vivo tumorigenesis\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP and dual-luciferase confirm HIF1α–KIAA1199 promoter interaction; functional rescue with 4MU; single lab\",\n      \"pmids\": [\"36209908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIAA1199 deficiency in bone marrow stromal cells (hMSCs) enhances osteoblast differentiation and increases bone mass in vivo. Mechanistically, KIAA1199 inhibits osteopontin production by osteoblasts via integrin-mediated AKT and ERK-MAPK intracellular signaling. KIAA1199 KO mice are protected from ovariectomy-induced bone loss and show accelerated healing of bone defects.\",\n      \"method\": \"KIAA1199 knockout mice, ectopic bone formation assay, in vitro osteoblast differentiation, Western blotting (AKT, ERK-MAPK), integrin inhibition, osteopontin expression analysis, micro-CT, biomechanical testing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with multiple skeletal phenotypes, mechanistic signaling dissection via pathway inhibitors, multiple orthogonal readouts across labs/models\",\n      \"pmids\": [\"37037828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CEMIP acts as a scaffold protein bridging MIB1 (an E3 ubiquitin ligase) and GRAF1. CEMIP interacts with the SH3 domain of GRAF1 through its 295-819aa domain and negatively regulates GRAF1 stability by facilitating MIB1-mediated ubiquitination and degradation of GRAF1. GRAF1 degradation activates CDC42/MAPK pathway-regulated EMT, promoting CRC metastasis.\",\n      \"method\": \"Co-immunoprecipitation (CEMIP-GRAF1-MIB1), domain mapping (295-819aa), ubiquitination assay, CDC42 activity assay, Western blotting, in vivo CRC metastasis model, CDC42 inhibitor\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP maps interacting domains, ubiquitination biochemically demonstrated, pharmacological and genetic rescue with CDC42 inhibitor; in vivo validation\",\n      \"pmids\": [\"36849460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human TMEM2 does not function as a catalytic hyaluronidase (in contrast to mouse TMEM2). In HEK293T cells, human HYBID and mouse TMEM2, but not human TMEM2, degraded extracellular HA. Chimeric domain analysis identified mouse GG domain residues His248 and Ala303 as critical for HA-degrading activity; replacing these with corresponding human TMEM2 residues (Asn248, Phe303) abolished mTMEM2 activity. In fibroblasts, hTMEM2 regulates HA metabolism by modulating HYBID and HAS2 expression.\",\n      \"method\": \"HEK293T transfection with human HYBID, mTMEM2, hTMEM2, and chimeric constructs; HA degradation assay; site-directed mutagenesis; siRNA knockdown of hTMEM2; HYBID/HAS2 expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in cells with domain-swapping mutagenesis, catalytic residue identification, loss-of-function; multiple constructs tested\",\n      \"pmids\": [\"37196767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CEMIP inhibits c-Myc ubiquitination by hindering the interaction between FBXW7 (E3 ubiquitin ligase) and c-Myc, increasing c-Myc stabilization and nuclear accumulation, thereby promoting glutamine-dependent SCLC cell proliferation.\",\n      \"method\": \"LC-MS/MS proteomics, co-immunoprecipitation (CEMIP-FBXW7-c-Myc), ubiquitination assay, c-Myc nuclear fractionation, GLS1 inhibitor CB-839, in vivo/in vitro functional assays\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and ubiquitination assay define mechanism; pharmacological inhibitor used for functional validation; single lab\",\n      \"pmids\": [\"36746261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ALKBH5 (m6A demethylase) negatively regulates CEMIP expression by reducing the stability of CEMIP mRNA. Reduced ALKBH5 in paclitaxel-resistant NSCLC cells leads to elevated CEMIP, promoting EMT and drug resistance; ALKBH5 overexpression reverses EMT and restores paclitaxel sensitivity.\",\n      \"method\": \"RNA-seq, RT-PCR, Western blotting, mRNA stability assay, ALKBH5 overexpression/knockdown, paclitaxel sensitivity assay, EMT marker analysis\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mRNA stability assay links m6A modification to CEMIP regulation; functional EMT and drug resistance phenotypes; single lab\",\n      \"pmids\": [\"38199493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A point mutation H783Y in KIAA1199 causes an unusual cytoplasmic distribution pattern distinct from the localization of wild-type protein, suggesting altered subcellular trafficking as a potential mechanism of hearing impairment.\",\n      \"method\": \"Site-directed mutagenesis, in vitro subcellular localization by microscopy\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization experiment with single mutant; no functional pathway mechanistic detail; single lab\",\n      \"pmids\": [\"14577002\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CEMIP (KIAA1199/HYBID) is a multifunctional protein that primarily mediates clathrin-dependent, CD44/HYAL-independent hyaluronan depolymerization through binding and intracellular trafficking of HA; it localizes to the endoplasmic reticulum (where it complexes with BiP and ITPR3 to modulate calcium signaling and promote PKCα-driven cell migration), to endosomes (where it scaffolds MEK1 to sustain ERK1/2 signaling), and to the cell surface (where its G8 domain binds ANXA1 to enable extracellular HA degradation); it acts as a scaffold for OGT/β-catenin O-GlcNAcylation, for MIB1/GRAF1 ubiquitin-mediated CDC42/MAPK activation, and for FBXW7/c-Myc stabilization; it drives anoikis resistance via ATF4-triggered PKCα phosphorylation of Bcl-2/Beclin1 autophagy and ITPR3/CaMKII/NRF2/SLC7A11-mediated ferroptosis resistance; it is transcriptionally regulated by NF-κB (via BCL-3/p65), HIF-2α, HIF1α lactylation, and ALKBH5-mediated m6A mRNA stability; in the tumor microenvironment, exosomal CEMIP conditions the brain pre-metastatic niche through endothelial branching and inflammation, drives immune evasion by acting as a clathrin adaptor for MHC-I internalization and lysosomal degradation, and promotes immunosuppressive neutrophil infiltration via TGFβR1/2-CXCL1/3 signaling; in normal physiology, it is required for HA homeostasis in skin, synovium, cartilage, cochlea, and brain, where its loss impairs hippocampal memory and dendritic spine density.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CEMIP (KIAA1199/HYBID) is the principal effector of CD44- and HYAL-independent hyaluronan (HA) depolymerization, binding HA directly and catabolizing it through an endo-β-N-acetylglucosaminidase-dependent clathrin-coated pit pathway in fibroblasts and tumor cells [#0]. Proper HA-degrading activity depends on intracellular trafficking governed by an N-terminal cleavable signal sequence and an ER-retention motif: in the ER, CEMIP complexes with the chaperone BiP and the calcium channel ITPR3, driving ER calcium leakage that activates PKCα to promote cell migration [#1, #3]. At the cell surface its G8 domain binds ANXA1 to anchor secreted CEMIP for extracellular HA degradation [#24], while in endosomes it scaffolds MEK1 to sustain ERK1/2 signaling [#13]. CEMIP transcription is tightly controlled by inflammatory and hypoxic inputs, including NF-κB downstream of IL-6/IL-1β [#9, #24], HIF-2α and lactylated HIF1α [#7, #30], with TGF-β1 suppressing it via PI3K-Akt to govern the molecular weight of newly synthesized HA [#8], and ALKBH5-mediated m6A demethylation destabilizing its mRNA [#35]. Beyond HA turnover, CEMIP functions as a versatile scaffold/adaptor coupling receptor and metabolic signaling: it potentiates EGFR-dependent Src/MEK/ERK signaling and EMT [#5], bridges OGT and β-catenin to enhance β-catenin O-GlcNAcylation and glutamine-metabolic reprogramming [#25], links MIB1 to GRAF1 for ubiquitin-mediated GRAF1 degradation and CDC42/MAPK-driven EMT [#32], binds PP2A to dephosphorylate stathmin and destabilize microtubules [#15], and acts as a clathrin adaptor for MHC-I internalization and lysosomal degradation to drive immune evasion [#28]. In cancer it confers anoikis, hypoxia, and ferroptosis resistance through ATF4/PKCα/Bcl-2/Beclin1 autophagy and ITPR3/CaMKII/NRF2/SLC7A11 axes [#26, #27], and exosomal CEMIP conditions the brain pre-metastatic niche via endothelial branching and perivascular inflammation [#18]. Physiologically, CEMIP is required for HA homeostasis in skin, synovium, brain, and bone, where its loss alters antimicrobial defense, dendritic spine density, arthritis susceptibility, and bone mass [#21, #22, #24, #31].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established CEMIP's core molecular identity by showing it mediates HA depolymerization independently of the canonical CD44/HYAL system, resolving the question of how cells catabolize HA through an unexpected clathrin-coated pit route.\",\n      \"evidence\": \"Glycosaminoglycan-binding assays, siRNA knockdown, cDNA transfection, and clathrin pathway inhibition in skin fibroblasts and disease specimens\",\n      \"pmids\": [\"23509262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism and whether CEMIP itself or an associated enzyme cleaves HA not fully resolved\", \"No structural model of the HA-binding/catalytic site\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the subcellular basis of CEMIP function, showing ER localization, BiP complex formation, and ER-retention-motif-dependent calcium leakage couple CEMIP to PKCα-driven migration, and that trafficking-determining sequences are required for HA depolymerization.\",\n      \"evidence\": \"SNAP-tag pull-down, FRET calcium measurement, mutagenesis of ER-retention/signal motifs, confocal imaging, and xenografts\",\n      \"pmids\": [\"23990668\", \"24269685\", \"23936024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single protein partitions between ER, surface, and secreted pools is unclear\", \"Interaction with ITPR3 from a single proteomics/Co-IP study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended CEMIP beyond HA biology into receptor signaling, identifying it as an NF-κB (BCL-3/p65) target that binds EGFR and Plexin A2 to sustain Src/MEK/ERK signaling, EGF-driven EMT, and protection from Semaphorin 3A death.\",\n      \"evidence\": \"ChIP, reciprocal Co-IP, siRNA/overexpression, and cell death assays\",\n      \"pmids\": [\"25366117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EGFR binding is direct vs. complex-mediated not established\", \"Link between HA-degrading activity and receptor scaffolding undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the hypoxic transcriptional control of CEMIP by showing HIF-2α (not HIF-1α) binds the CEMIP promoter and that Jarid1A-dependent H3K4me3 changes gate expression, positioning CEMIP as a hypoxia-driven migration effector.\",\n      \"evidence\": \"ChIP, isoform-specific knockdown, H3K4me3 chromatin analysis, and migration assays\",\n      \"pmids\": [\"26009875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with later HIF1α-lactylation regulation not addressed\", \"Context dependence of HIF isoform usage unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected CEMIP to growth-factor and cytokine control of HA size, showing TGF-β1 suppresses HYBID via PI3K-Akt while inducing HAS, determining whether high- or low-MW HA accumulates in normal vs. arthritic synovium.\",\n      \"evidence\": \"siRNA, pathway-specific inhibitors, HA size-exclusion chromatography, and clinical tissue correlation\",\n      \"pmids\": [\"26518873\", \"27981209\", \"28179576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcription factors downstream of these pathways at the CEMIP locus not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified CEMIP as a signaling hub in normal cell physiology, controlling Nrg1/MEK/ERK-driven Schwann cell dedifferentiation and myelin clearance, and binding WBP11/PTP4A3 to gate FGFR4/Wnt and EGFR signaling.\",\n      \"evidence\": \"RNAi, conditional Cre-lox knockout mice, Nrg1 stimulation, Co-IP, and rescue assays\",\n      \"pmids\": [\"28699206\", \"30626935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CEMIP positions MEK1/ERK in Schwann cells vs. tumor endosomes not unified\", \"WBP11/PTP4A3 interactions from a single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined endosomal scaffolding of MEK1 as the basis for CEMIP-driven MEK-inhibitor resistance, and revealed multiple scaffold functions (PP2A/stathmin/microtubule destabilization; BiP-promoter-driven hypoxia adaptation) underlying motility and survival.\",\n      \"evidence\": \"Endosomal fractionation, Co-IP, organoids, in vivo models, phosphatase/microtubule assays, and promoter reporters\",\n      \"pmids\": [\"29915160\", \"30202098\", \"29505302\", \"31303964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CEMIP simultaneously engages PP2A, MEK1, and metabolic programs not integrated\", \"Several functional links rest on single-lab data\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that CEMIP, not the related TMEM2, is the indispensable HA depolymerase in human fibroblasts, with TMEM2 acting only as an expression modulator, clarifying the division of labor in HA catabolism.\",\n      \"evidence\": \"Separate siRNA knockdowns, HA depolymerization assays across cell lines\",\n      \"pmids\": [\"30241936\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional knockdown without reconstitution\", \"Catalytic vs. trafficking contribution of CEMIP not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established physiological and microenvironmental roles, showing exosomal CEMIP conditions the brain pre-metastatic niche, and CEMIP drives β-catenin-dependent chondrocyte transdifferentiation, hMSC migration, and metabolic reprogramming.\",\n      \"evidence\": \"Exosome proteomics with depletion/rescue, RNA-seq, shRNA/CRISPR, signaling rescue, and in vivo metastasis models\",\n      \"pmids\": [\"31685984\", \"30718510\", \"30755597\", \"29505302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of CEMIP exosomal loading and uptake unknown\", \"How extracellular CEMIP acts on recipient cells not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Used knockout mice to define normal physiological requirements for CEMIP-mediated HA turnover in skin antimicrobial defense and brain synaptic structure, and dissected histamine-driven CEMIP induction in skin.\",\n      \"evidence\": \"Cemip knockout mice with S. aureus challenge, Golgi-Cox/doublecortin staining, and pharmacological H1-receptor/PKCδ/PI3K dissection\",\n      \"pmids\": [\"31914398\", \"30060951\", \"31949043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Brain phenotype from a single lab without independent replication\", \"Causal link between HA accumulation and synaptic deficits incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped the extracellular HA-degradation machinery to a G8-domain/ANXA1 membrane-tethering mechanism required in vivo for arthritis pathology, and identified CEMIP as an OGT adaptor enabling β-catenin O-GlcNAcylation and glutamine reprogramming.\",\n      \"evidence\": \"G8-deleted vs. full-length rescue in knockout mice with collagen-induced arthritis; Co-IP of CEMIP-OGT-β-catenin with O-GlcNAcylation assays and metastasis models\",\n      \"pmids\": [\"33473125\", \"34608265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of G8/ANXA1 binding not resolved\", \"Whether OGT scaffolding and HA degradation are coupled unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined CEMIP-driven stress-resistance and immune-evasion mechanisms in cancer: ATF4/PKCα/Bcl-2/Beclin1 autophagy for anoikis resistance, ITPR3/CaMKII/NRF2/SLC7A11 for ferroptosis resistance, clathrin-adaptor-mediated MHC-I degradation, TGFβR-CXCL1/3 neutrophil recruitment, and HIF1α-lactylation-driven angiogenesis.\",\n      \"evidence\": \"Co-IP, proximity ligation, flow cytometry, CD8+ T-cell cytotoxicity, ChIP/dual-luciferase, and in vivo metastasis models\",\n      \"pmids\": [\"35013120\", \"35363929\", \"36596591\", \"35108400\", \"36209908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Most stress-resistance chains validated in single labs\", \"How one scaffold mediates such divergent adaptor functions unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established CEMIP as a regulator of ubiquitin-ligase activity—bridging MIB1 to GRAF1 for degradation and blocking FBXW7-mediated c-Myc turnover—and defined skeletal physiology where CEMIP loss increases osteoblast differentiation and bone mass; human TMEM2 was shown to be catalytically inactive unlike mouse.\",\n      \"evidence\": \"Domain-mapped Co-IP, ubiquitination assays, CDC42/integrin signaling dissection, knockout mice with micro-CT, and HEK293T reconstitution with domain-swap mutagenesis\",\n      \"pmids\": [\"36849460\", \"36746261\", \"37037828\", \"37196767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of scaffold-directed ubiquitination unknown\", \"Whether CEMIP's catalytic HA mechanism parallels the TMEM2 GG-domain chemistry untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added post-transcriptional control by showing ALKBH5-mediated m6A demethylation destabilizes CEMIP mRNA, linking loss of this regulation to EMT and paclitaxel resistance.\",\n      \"evidence\": \"mRNA stability assays, ALKBH5 overexpression/knockdown, and drug-sensitivity/EMT marker analysis in NSCLC\",\n      \"pmids\": [\"38199493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A sites on CEMIP mRNA not mapped\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying biochemical question—how CEMIP's intrinsic HA-depolymerizing activity mechanistically relates to its many protein-scaffold/adaptor functions, and what structural features partition it among ER, endosome, surface, and secreted pools—remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of CEMIP or its catalytic/HA-binding site\", \"No reconstituted enzymatic assay distinguishing direct catalysis from adaptor recruitment\", \"Mechanism partitioning CEMIP across compartments undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [13, 25, 28, 32]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 34]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 24]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 9, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [14, 25, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 13, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 24, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [28, 29]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 8, 16]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 28]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BiP\", \"ITPR3\", \"EGFR\", \"OGT\", \"CTNNB1\", \"MEK1\", \"PP2A\", \"MIB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}