{"gene":"PROM1","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2000,"finding":"AC133 (PROM1/CD133) is a 5-transmembrane domain cell-surface glycoprotein that localizes selectively to plasma membrane protrusions (microvilli and filopodia) in epithelial and non-epithelial cells, with this localization being independent of epithelial phenotype—ectopic expression in fibroblasts also targets the protein to membrane protrusions.","method":"Immunofluorescence, immunoprecipitation, and electron microscopy of Caco-2 epithelial cells and transfected fibroblasts; flow cytometry of murine CD34+ bone marrow progenitors","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal imaging methods (IF, EM, IP) with consistent results across multiple cell types","pmids":["10681530"],"is_preprint":false},{"year":2002,"finding":"AC133-2, a novel isoform of PROM1 generated by alternative mRNA splicing (deletion of a 27-nucleotide exon), is glycosylated and transported to the plasma membrane; AC133-2 is the isoform expressed on hematopoietic stem cells and co-expressed with β1 integrin in the basal layer of neonatal epidermis, with its expression lost upon differentiation.","method":"cDNA cloning, expression in HEK293 cells, glycosylation analysis, RT-PCR across tissues, flow cytometry of fetal liver/bone marrow/peripheral blood HSCs, immunofluorescence of neonatal epidermis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct biochemical characterization with multiple orthogonal methods across multiple tissue types","pmids":["12042327"],"is_preprint":false},{"year":2015,"finding":"Nucleolin directly activates CD133 transcription via specific interaction with the tissue-dependent CD133 promoter P1, thereby controlling surface AC133 expression on CD34+ hematopoietic stem/progenitor cells; nucleolin also elevates active β-catenin, active Akt, and Bcl-2 levels in a partially β-catenin-dependent manner in these cells.","method":"Chromatin immunoprecipitation (nucleolin-P1 promoter interaction), promoter reporter assays, siRNA knockdown, flow cytometry, colony-forming unit assays, long-term culture-initiating cell assays","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 — ChIP plus functional assays with multiple orthogonal readouts in primary HSPCs","pmids":["26183533"],"is_preprint":false},{"year":2018,"finding":"Prominin-1 (CD133) overexpression increases the number and alters the morphology of microvilli (branched, knob-like) through interaction with PI3K and Arp2/3 complex; mutation of tyrosine 828 impairs phosphorylation of prominin-1 and abolishes these interactions and microvillar phenotypes; ganglioside-binding site mutations stimulate branched microvilli, indicating a prominin-1–ganglioside–PI3K–Arp2/3 regulatory axis for microvillar architecture.","method":"High-resolution light and electron microscopy of MDCK cells overexpressing wild-type and mutant prominin-1; co-immunoprecipitation with PI3K and Arp2/3; site-directed mutagenesis (Y828 and ganglioside-binding site); siRNA knockdown in primary hematopoietic stem cells","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution with mutagenesis, reciprocal co-IP, and high-resolution structural imaging with multiple mutant validations","pmids":["30328220"],"is_preprint":false},{"year":2019,"finding":"Pericentrosomal/recycling-endosomal CD133 captures GABARAP (an autophagy initiator) and inhibits GABARAP-mediated ULK1 activation, thereby suppressing autophagy initiation; when Src family kinase activity is weak, CD133 interacts with HDAC6 and is transported to the pericentrosomal region via the dynein-based trafficking system; pericentrosomal CD133 thus suppresses primary cilium formation and neurite outgrowth by inhibiting autophagy.","method":"Co-immunoprecipitation (CD133–HDAC6, CD133–GABARAP), subcellular fractionation/confocal imaging, dynein inhibition, Src kinase manipulation, ULK1 phosphorylation assays, primary cilium and neurite outgrowth phenotypic assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with mechanistic pathway dissection and multiple functional phenotypic readouts","pmids":["30783186"],"is_preprint":false},{"year":2018,"finding":"CD133 forms a complex with E-cadherin and β-catenin (shown by immunoprecipitation), and CD133 knockdown reduces β-catenin levels and TCF/LEF promoter activation, indicating that CD133 acts as a permissive factor for Wnt/β-catenin signaling by preventing β-catenin degradation in the cytoplasm; loss of CD133 impairs renal tubular cell proliferation after cisplatin injury and promotes cellular senescence.","method":"Co-immunoprecipitation (CD133–E-cadherin–β-catenin complex), siRNA knockdown, TCF/LEF luciferase reporter assay, Wnt pathway activation assays, RNA sequencing, nephroshere generation, senescence assays","journal":"Stem cells translational medicine","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus reporter assay plus KD phenotype, multiple orthogonal methods","pmids":["29431914"],"is_preprint":false},{"year":2020,"finding":"Prom1 interacts with the type I TGF-β receptor ALK4, and they synergistically induce phosphorylation of Smad2; Prom1 overexpression downregulates cholesterol metabolism genes and reduces cellular cholesterol in a Smad-pathway-dependent manner, promoting axon regeneration; genetic deletion of Prom1 in mice inhibits axon regeneration in DRG cultures and in the sciatic nerve.","method":"Co-immunoprecipitation (Prom1–ALK4), Smad2 phosphorylation assays, Prom1 knockout mice, AAV-mediated overexpression in DRG neurons and in vivo sciatic nerve model, cholesterol assays, gene expression profiling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP binding partner identification, in vivo KO phenotype, in vivo and in vitro gain-of-function, mechanistic pathway dissection","pmids":["32554499"],"is_preprint":false},{"year":2013,"finding":"CD133 silencing by lentiviral shRNA in patient-derived GBM neurospheres impairs self-renewal and tumorigenic capacity; CD133 undergoes interconversion between cytoplasmic and plasma-membrane localizations in neurosphere cells (not a strict hierarchy between CD133+ and CD133− cells).","method":"Lentivirus-mediated shRNA knockdown, neurosphere self-renewal assays, xenograft tumor formation, immunofluorescence subcellular localization","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype, but single lab","pmids":["23307586"],"is_preprint":false},{"year":2010,"finding":"CD133 suppresses neuroblastoma cell differentiation (neurite extension and differentiation marker expression) and this suppression is mechanistically dependent on p38MAPK and PI3K/Akt pathways; CD133 suppresses RET tyrosine kinase transcription, and RET overexpression rescues CD133-mediated inhibition of neurite elongation, placing CD133 upstream of RET in a differentiation-regulatory axis.","method":"CD133 overexpression/knockdown in NB cell lines and primary tumor spheres, pathway inhibitor experiments (p38MAPK, PI3K/Akt), RET rescue experiments, gene expression analysis, colony formation and xenograft assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis via rescue experiment, pathway inhibitors, defined phenotypic readouts; single lab","pmids":["20818439"],"is_preprint":false},{"year":2018,"finding":"CD133 expression increases IL-1β expression and its downstream chemokines CCL3, CXCL3, and CXCL5 in glioma cells, leading to increased neutrophil recruitment in vitro and in vivo; this places CD133 upstream of IL-1β signaling in modulation of the glioma tumor microenvironment.","method":"Forced CD133 expression in U87MG glioma cells, trans-well neutrophil recruitment assays, in vivo xenograft assays, gene expression analysis, correlation analysis in patient malignant glioma data","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function with in vitro and in vivo functional readouts; single lab","pmids":["28736425"],"is_preprint":false},{"year":2018,"finding":"CD133 regulates RhoA and Rac1 GTPase activities to control microvesicle (MV) budding from the plasma membrane; EGF-induced NF-κB activation upregulates CD133 expression, which then modulates MV release; CD133-containing MVs from KRAS-mutant colon cancer cells deliver mutant KRAS to adjacent cells, activating KRAS downstream signaling and conferring chemoresistance to anti-EGFR drugs.","method":"siRNA knockdown and overexpression of CD133, nanoparticle tracking analysis of MV size and number, GTPase activity assays (RhoA, Rac1), KRAS oncoprotein transfer experiments, proliferation/motility assays with anti-EGFR drugs","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic dissection with GTPase assays and functional transfer experiments; single lab","pmids":["30521383"],"is_preprint":false},{"year":2008,"finding":"CD133 transcription is controlled by both promoter CpG island methylation and histone modifications; CD133+ ovarian cancer cells maintain a hypomethylated promoter state, whereas CD133− progeny show increased promoter methylation; treatment with DNA methyltransferase and HDAC inhibitors synergistically restores CD133 surface expression in CD133− cells.","method":"Bisulfite sequencing, ChIP for histone marks, flow cytometry after epigenetic drug treatment, cell sorting, xenograft assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — direct epigenetic mechanism established with bisulfite sequencing and ChIP; single lab","pmids":["18836486"],"is_preprint":false},{"year":2008,"finding":"Promoter CpG island DNA methylation heterogeneously controls CD133 expression within individual colon cancer and glioblastoma cell lines; differential histone modification marks (active vs. repressed) accompany DNA methylation changes; this promoter methylation signature is tumor-specific and absent from normal brain and colon.","method":"Bisulfite sequencing, ChIP for histone marks, FACS-sorted CD133+/− cell populations, comparative methylation analysis of tumors vs. normal tissue","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — direct epigenetic characterization with ChIP and bisulfite sequencing in sorted populations; single lab","pmids":["18829568"],"is_preprint":false},{"year":2008,"finding":"DNA hypomethylation of the CD133 P1, P2, and P3 proximal promoters is an important determinant of CD133 expression in glioblastomas; P1 region (flanking exon 1A) shows highest promoter activity and is inactivated by in vitro methylation; treatment with 5-azacytidine and/or valproic acid restores CD133 mRNA in glioma cells.","method":"Bisulfite sequencing, promoter-reporter luciferase assays with in vitro methylation, 5-azacytidine and valproic acid treatments, RT-PCR","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 — promoter activity assays with direct methylation manipulation; single lab","pmids":["18679414"],"is_preprint":false},{"year":2013,"finding":"CD133 is associated with cholesterol-binding activity and is selectively concentrated in cholesterol-rich plasma membrane microdomains (lipid rafts) within membrane protrusions.","method":"Biochemical fractionation and cholesterol interaction studies described in review context, supported by prior experimental data in cited literature","journal":"Advances in experimental medicine and biology","confidence":"Low","confidence_rationale":"Tier 3 — review paper summarizing biochemical cholesterol-binding data without primary experimental detail in this paper","pmids":["23161072"],"is_preprint":false},{"year":2015,"finding":"An intronic 10 bp deletion in PROM1 intron 21 disrupts an SRSF2 splicing factor recognition site and causes complete exon 22 skipping in vitro, leading to a frameshift and premature termination codon, establishing intronic splicing mutations as a mechanism for PROM1 loss-of-function in cone-rod dystrophy.","method":"Minigene splicing reporter assay, bioinformatic SRSF2 binding site prediction, homozygosity mapping, direct sequencing","journal":"Molecular vision","confidence":"Medium","confidence_rationale":"Tier 1 — functional splicing assay with minigene reconstitution; single lab but mechanistically definitive","pmids":["26702251"],"is_preprint":false},{"year":2015,"finding":"A deep intronic variant in PROM1 intron 18 activates a pseudoexon through altered splicing, leading to a premature termination codon and functional null allele, causing autosomal recessive cone-rod dystrophy; this was confirmed by whole-genome sequencing and minigene splicing reporter assays.","method":"Whole-genome sequencing, minigene splicing reporter (in silico + in vitro functional analysis), homozygosity mapping","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 1 — functional minigene splicing validation; single family/lab","pmids":["26153215"],"is_preprint":false},{"year":2018,"finding":"The c.C1902G (p.Y634X) nonsense mutation in PROM1 results in a truncated, labile, and mislocalized protein as shown by confocal microscopy of transfected cells, while a splice-site mutation (c.C1682+3A>G) disrupts mRNA splicing as shown by bridge-PCR; both mutations underlie hereditary macular and rod-cone dystrophy.","method":"Whole exome sequencing, transient transfection of mutant PROM1 constructs in cultured cells, confocal microscopy for protein localization, bridge-PCR for splice analysis","journal":"Graefe's archive for clinical and experimental ophthalmology","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional characterization of protein localization and splicing in cultured cells; single lab","pmids":["30588538"],"is_preprint":false}],"current_model":"PROM1 (CD133/prominin-1) is a pentaspan transmembrane cholesterol-binding glycoprotein that localizes constitutively to plasma membrane protrusions (microvilli, filopodia) via interactions with gangliosides, PI3K, and the Arp2/3 complex (regulated by phosphorylation of Y828); in the cytoplasm it traffics via dynein/HDAC6 to pericentrosomal recycling endosomes where it sequesters GABARAP to inhibit autophagy initiation and suppress differentiation; it forms a complex with E-cadherin and β-catenin to promote Wnt/β-catenin signaling, interacts with ALK4 to drive Smad2 phosphorylation and cholesterol downregulation supporting axon regeneration, and modulates microvesicle release by regulating RhoA and Rac1 GTPase activity; its transcription is controlled by tissue-specific alternative promoters whose activity is regulated by CpG methylation (written/erased by DNMT/TET machinery) and histone modifications, with nucleolin acting as a direct transcriptional activator at the P1 promoter in hematopoietic stem cells."},"narrative":{"teleology":[{"year":2000,"claim":"Establishing PROM1 as a pentaspan transmembrane glycoprotein with an intrinsic capacity to target plasma membrane protrusions (microvilli, filopodia) independently of cell type resolved where the protein resides and that its localization is cell-autonomous.","evidence":"Immunofluorescence, immunoprecipitation, and electron microscopy in Caco-2 cells and transfected fibroblasts","pmids":["10681530"],"confidence":"High","gaps":["Mechanism by which PROM1 is targeted to protrusions was unknown","No interacting partners identified at this stage"]},{"year":2002,"claim":"Identification of the AC133-2 splice isoform and its selective expression on hematopoietic stem cells, with loss upon differentiation, established PROM1 as a stem-cell-associated marker with regulated alternative splicing.","evidence":"cDNA cloning, glycosylation analysis, RT-PCR across tissues, flow cytometry of HSCs, immunofluorescence of neonatal epidermis","pmids":["12042327"],"confidence":"High","gaps":["Functional consequence of the 27-nt exon deletion was not determined","Whether expression loss upon differentiation is transcriptional or post-transcriptional was unclear"]},{"year":2008,"claim":"Three independent studies converged to show that PROM1 transcription is controlled by CpG methylation of its alternative promoters (P1–P3) together with histone modifications, explaining the on/off switching of CD133 expression in tumors versus normal tissues and between sorted CD133+ and CD133− populations.","evidence":"Bisulfite sequencing, ChIP for histone marks, promoter-reporter assays with in vitro methylation, epigenetic drug treatments in ovarian cancer, glioblastoma, and colon cancer lines","pmids":["18836486","18829568","18679414"],"confidence":"Medium","gaps":["Identity of the DNMTs and demethylases responsible in vivo was not established","Chromatin remodelers acting at PROM1 promoters were not identified"]},{"year":2010,"claim":"Showing that CD133 suppresses neuroblastoma differentiation through p38MAPK and PI3K/Akt pathways and represses RET transcription established a signaling axis through which PROM1 actively inhibits differentiation rather than merely marking undifferentiated cells.","evidence":"Overexpression/knockdown in neuroblastoma lines, pathway inhibitor epistasis, RET rescue experiments","pmids":["20818439"],"confidence":"Medium","gaps":["Direct biochemical mechanism linking CD133 to p38MAPK and PI3K activation was not defined","Whether RET repression is transcriptionally direct was not resolved"]},{"year":2013,"claim":"Demonstrating that CD133 knockdown impairs glioblastoma neurosphere self-renewal and that CD133 dynamically interconverts between surface and cytoplasmic pools showed that PROM1 function involves regulated subcellular trafficking rather than a fixed surface identity.","evidence":"Lentiviral shRNA knockdown, neurosphere assays, xenograft formation, immunofluorescence localization","pmids":["23307586"],"confidence":"Medium","gaps":["Trafficking machinery responsible for surface–cytoplasm interconversion was not identified","Whether cytoplasmic CD133 has distinct signaling functions was unknown"]},{"year":2015,"claim":"Two studies identified deep intronic mutations in PROM1 that disrupt splicing (exon skipping and pseudoexon activation) to produce null alleles causing autosomal recessive cone-rod dystrophy, establishing PROM1 as essential for photoreceptor maintenance.","evidence":"Minigene splicing reporter assays, whole-genome sequencing, homozygosity mapping in affected families","pmids":["26702251","26153215"],"confidence":"Medium","gaps":["Photoreceptor-specific function of PROM1 protein was not mechanistically dissected","Animal model validation of these specific splicing mutations was not performed"]},{"year":2015,"claim":"Identifying nucleolin as a direct transcriptional activator of the PROM1 P1 promoter in HSPCs, with downstream elevation of active β-catenin and Akt, linked PROM1 transcription to a defined upstream regulator and explained its tissue-specific expression in the hematopoietic compartment.","evidence":"ChIP for nucleolin at P1 promoter, promoter-reporter assays, siRNA knockdown, colony-forming and LTC-IC assays in primary HSPCs","pmids":["26183533"],"confidence":"High","gaps":["Whether nucleolin regulation of PROM1 occurs in non-hematopoietic tissues was not tested","Other transcription factors cooperating with nucleolin at P1 were not identified"]},{"year":2018,"claim":"Dissecting how PROM1 shapes microvillar architecture through Y828 phosphorylation-dependent PI3K and Arp2/3 recruitment, with ganglioside binding providing an additional regulatory input, provided the first molecular mechanism for PROM1's constitutive protrusion targeting.","evidence":"High-resolution microscopy, co-IP with PI3K and Arp2/3, Y828 and ganglioside-binding-site mutagenesis in MDCK cells","pmids":["30328220"],"confidence":"High","gaps":["Structural basis of the PROM1–ganglioside interaction was not resolved","Kinase(s) responsible for Y828 phosphorylation were not identified"]},{"year":2018,"claim":"Showing that CD133 forms a complex with E-cadherin and β-catenin and that its loss reduces β-catenin levels and TCF/LEF activity established PROM1 as a permissive factor for canonical Wnt signaling and linked it to renal tubular repair after injury.","evidence":"Co-IP of CD133–E-cadherin–β-catenin, siRNA knockdown, TCF/LEF luciferase reporter, senescence assays in renal cells","pmids":["29431914"],"confidence":"High","gaps":["Whether PROM1 directly stabilizes β-catenin or acts indirectly through E-cadherin sequestration was not distinguished","In vivo renal injury model with genetic PROM1 deletion was not performed"]},{"year":2018,"claim":"Demonstrating that CD133 regulates RhoA and Rac1 GTPase activities to control microvesicle budding, and that CD133-containing microvesicles transfer oncogenic KRAS to recipient cells, revealed a role for PROM1 in intercellular cargo transfer via extracellular vesicles.","evidence":"siRNA/overexpression of CD133, nanoparticle tracking, GTPase activity assays, functional KRAS transfer experiments in colon cancer cells","pmids":["30521383"],"confidence":"Medium","gaps":["How PROM1 modulates GTPase activity (direct GAP/GEF interaction vs. indirect) was not resolved","In vivo relevance of PROM1-mediated microvesicle release was not tested"]},{"year":2019,"claim":"Identifying the HDAC6/dynein-dependent trafficking of CD133 to pericentrosomal recycling endosomes, where it sequesters GABARAP to block ULK1 activation and autophagy initiation, provided a unified mechanism explaining how PROM1 suppresses both primary ciliogenesis and differentiation.","evidence":"Co-IP (CD133–HDAC6, CD133–GABARAP), confocal imaging, dynein inhibition, Src kinase manipulation, ULK1 phosphorylation assays","pmids":["30783186"],"confidence":"High","gaps":["Stoichiometry and direct vs. bridged nature of the CD133–GABARAP interaction were not determined","Whether autophagy suppression fully accounts for PROM1's anti-differentiation activity was not tested"]},{"year":2020,"claim":"Showing that PROM1 interacts with ALK4 to synergistically activate Smad2 and downregulate cholesterol metabolism, promoting axon regeneration in vivo, extended PROM1's signaling repertoire to TGF-β/Smad signaling and neuronal repair.","evidence":"Co-IP (Prom1–ALK4), Prom1 knockout mice, AAV-mediated overexpression in DRG neurons and sciatic nerve model, cholesterol assays","pmids":["32554499"],"confidence":"High","gaps":["Whether PROM1 acts as a co-receptor or modulator of ALK4 kinase activity was not distinguished","Role of cholesterol reduction versus other Smad2 targets in regeneration was not separated"]},{"year":null,"claim":"Major unresolved questions include the structural basis of PROM1's cholesterol and ganglioside binding, the identity of kinases phosphorylating Y828, whether the autophagy-suppressive and Wnt-stabilizing functions operate in the same or distinct cellular contexts, and how PROM1 loss specifically causes photoreceptor degeneration at the cellular level.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of PROM1","Kinase for Y828 phosphorylation unidentified","Photoreceptor-specific mechanism of PROM1 function not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[14,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[4]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,8]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,11,12,13]}],"complexes":["E-cadherin–β-catenin complex"],"partners":["CDH1","CTNNB1","HDAC6","GABARAP","ACVR1B","NCL","PIK3CA","ACTR2"],"other_free_text":[]},"mechanistic_narrative":"PROM1 (CD133/prominin-1) is a pentaspan transmembrane glycoprotein that organizes plasma membrane protrusion architecture and integrates signaling pathways controlling stemness, differentiation, and autophagy. At the cell surface, PROM1 localizes constitutively to microvilli and filopodia via a phosphorylation-dependent (Y828) interaction with PI3K and the Arp2/3 complex, regulated by ganglioside binding, and forms a complex with E-cadherin and β-catenin to sustain Wnt/β-catenin signaling [PMID:30328220, PMID:29431914]; it also interacts with ALK4 to activate Smad2 phosphorylation, downregulate cholesterol, and promote axon regeneration [PMID:32554499], and modulates microvesicle release by regulating RhoA and Rac1 GTPase activities [PMID:30521383]. Intracellularly, PROM1 traffics via HDAC6 and dynein to pericentrosomal recycling endosomes where it sequesters GABARAP to inhibit autophagy initiation and suppress differentiation [PMID:30783186]. Loss-of-function mutations in PROM1, including nonsense, splice-site, and deep intronic variants, cause autosomal recessive cone-rod dystrophy and macular dystrophy [PMID:26702251, PMID:30588538]."},"prefetch_data":{"uniprot":{"accession":"O43490","full_name":"Prominin-1","aliases":["Antigen AC133","Prominin-like protein 1"],"length_aa":865,"mass_kda":97.2,"function":"May play a role in cell differentiation, proliferation and apoptosis (PubMed:24556617). Binds cholesterol in cholesterol-containing plasma membrane microdomains and may play a role in the organization of the apical plasma membrane in epithelial cells. During early retinal development acts as a key regulator of disk morphogenesis. Involved in regulation of MAPK and Akt signaling pathways. In neuroblastoma cells suppresses cell differentiation such as neurite outgrowth in a RET-dependent manner (PubMed:20818439)","subcellular_location":"Apical cell membrane; Cell projection, microvillus membrane; Cell projection, cilium, photoreceptor outer segment; Endoplasmic reticulum; Endoplasmic reticulum-Golgi intermediate compartment","url":"https://www.uniprot.org/uniprotkb/O43490/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PROM1","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/PROM1","total_profiled":1310},"omim":[{"mim_id":"617160","title":"PROMININ 2; PROM2","url":"https://www.omim.org/entry/617160"},{"mim_id":"616352","title":"ACYL-CoA-BINDING DOMAIN-CONTAINING PROTEIN 6; ACBD6","url":"https://www.omim.org/entry/616352"},{"mim_id":"616333","title":"WNT SIGNALING PATHWAY ACTIVATING NONCODING RNA; WSPAR","url":"https://www.omim.org/entry/616333"},{"mim_id":"612657","title":"CONE-ROD DYSTROPHY 12; CORD12","url":"https://www.omim.org/entry/612657"},{"mim_id":"612095","title":"RETINITIS PIGMENTOSA 41; RP41","url":"https://www.omim.org/entry/612095"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":252.8}],"url":"https://www.proteinatlas.org/search/PROM1"},"hgnc":{"alias_symbol":["AC133","CD133","RP41","CORD12"],"prev_symbol":["PROML1","MCDR2","STGD4"]},"alphafold":{"accession":"O43490","domains":[{"cath_id":"-","chopping":"49-215_421-540_784-818","consensus_level":"medium","plddt":89.5589,"start":49,"end":818},{"cath_id":"-","chopping":"264-353_611-740","consensus_level":"medium","plddt":92.5092,"start":264,"end":740}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43490","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43490-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43490-F1-predicted_aligned_error_v6.png","plddt_mean":85.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PROM1","jax_strain_url":"https://www.jax.org/strain/search?query=PROM1"},"sequence":{"accession":"O43490","fasta_url":"https://rest.uniprot.org/uniprotkb/O43490.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43490/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43490"}},"corpus_meta":[{"pmid":"10648408","id":"PMC_10648408","title":"Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors.","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10648408","citation_count":1789,"is_preprint":false},{"pmid":"9389720","id":"PMC_9389720","title":"AC133, a novel marker for human hematopoietic stem and progenitor cells.","date":"1997","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9389720","citation_count":1401,"is_preprint":false},{"pmid":"10807776","id":"PMC_10807776","title":"In vitro differentiation of endothelial cells from AC133-positive progenitor cells.","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10807776","citation_count":781,"is_preprint":false},{"pmid":"17955491","id":"PMC_17955491","title":"CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells.","date":"2008","source":"International journal of 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reports","url":"https://pubmed.ncbi.nlm.nih.gov/30126854","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49435,"output_tokens":4772,"usd":0.109942},"stage2":{"model":"claude-opus-4-6","input_tokens":8323,"output_tokens":3433,"usd":0.19116},"total_usd":0.301102,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"AC133 (PROM1/CD133) is a 5-transmembrane domain cell-surface glycoprotein that localizes selectively to plasma membrane protrusions (microvilli and filopodia) in epithelial and non-epithelial cells, with this localization being independent of epithelial phenotype—ectopic expression in fibroblasts also targets the protein to membrane protrusions.\",\n      \"method\": \"Immunofluorescence, immunoprecipitation, and electron microscopy of Caco-2 epithelial cells and transfected fibroblasts; flow cytometry of murine CD34+ bone marrow progenitors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal imaging methods (IF, EM, IP) with consistent results across multiple cell types\",\n      \"pmids\": [\"10681530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"AC133-2, a novel isoform of PROM1 generated by alternative mRNA splicing (deletion of a 27-nucleotide exon), is glycosylated and transported to the plasma membrane; AC133-2 is the isoform expressed on hematopoietic stem cells and co-expressed with β1 integrin in the basal layer of neonatal epidermis, with its expression lost upon differentiation.\",\n      \"method\": \"cDNA cloning, expression in HEK293 cells, glycosylation analysis, RT-PCR across tissues, flow cytometry of fetal liver/bone marrow/peripheral blood HSCs, immunofluorescence of neonatal epidermis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical characterization with multiple orthogonal methods across multiple tissue types\",\n      \"pmids\": [\"12042327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nucleolin directly activates CD133 transcription via specific interaction with the tissue-dependent CD133 promoter P1, thereby controlling surface AC133 expression on CD34+ hematopoietic stem/progenitor cells; nucleolin also elevates active β-catenin, active Akt, and Bcl-2 levels in a partially β-catenin-dependent manner in these cells.\",\n      \"method\": \"Chromatin immunoprecipitation (nucleolin-P1 promoter interaction), promoter reporter assays, siRNA knockdown, flow cytometry, colony-forming unit assays, long-term culture-initiating cell assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus functional assays with multiple orthogonal readouts in primary HSPCs\",\n      \"pmids\": [\"26183533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Prominin-1 (CD133) overexpression increases the number and alters the morphology of microvilli (branched, knob-like) through interaction with PI3K and Arp2/3 complex; mutation of tyrosine 828 impairs phosphorylation of prominin-1 and abolishes these interactions and microvillar phenotypes; ganglioside-binding site mutations stimulate branched microvilli, indicating a prominin-1–ganglioside–PI3K–Arp2/3 regulatory axis for microvillar architecture.\",\n      \"method\": \"High-resolution light and electron microscopy of MDCK cells overexpressing wild-type and mutant prominin-1; co-immunoprecipitation with PI3K and Arp2/3; site-directed mutagenesis (Y828 and ganglioside-binding site); siRNA knockdown in primary hematopoietic stem cells\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution with mutagenesis, reciprocal co-IP, and high-resolution structural imaging with multiple mutant validations\",\n      \"pmids\": [\"30328220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Pericentrosomal/recycling-endosomal CD133 captures GABARAP (an autophagy initiator) and inhibits GABARAP-mediated ULK1 activation, thereby suppressing autophagy initiation; when Src family kinase activity is weak, CD133 interacts with HDAC6 and is transported to the pericentrosomal region via the dynein-based trafficking system; pericentrosomal CD133 thus suppresses primary cilium formation and neurite outgrowth by inhibiting autophagy.\",\n      \"method\": \"Co-immunoprecipitation (CD133–HDAC6, CD133–GABARAP), subcellular fractionation/confocal imaging, dynein inhibition, Src kinase manipulation, ULK1 phosphorylation assays, primary cilium and neurite outgrowth phenotypic assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with mechanistic pathway dissection and multiple functional phenotypic readouts\",\n      \"pmids\": [\"30783186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD133 forms a complex with E-cadherin and β-catenin (shown by immunoprecipitation), and CD133 knockdown reduces β-catenin levels and TCF/LEF promoter activation, indicating that CD133 acts as a permissive factor for Wnt/β-catenin signaling by preventing β-catenin degradation in the cytoplasm; loss of CD133 impairs renal tubular cell proliferation after cisplatin injury and promotes cellular senescence.\",\n      \"method\": \"Co-immunoprecipitation (CD133–E-cadherin–β-catenin complex), siRNA knockdown, TCF/LEF luciferase reporter assay, Wnt pathway activation assays, RNA sequencing, nephroshere generation, senescence assays\",\n      \"journal\": \"Stem cells translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus reporter assay plus KD phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"29431914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Prom1 interacts with the type I TGF-β receptor ALK4, and they synergistically induce phosphorylation of Smad2; Prom1 overexpression downregulates cholesterol metabolism genes and reduces cellular cholesterol in a Smad-pathway-dependent manner, promoting axon regeneration; genetic deletion of Prom1 in mice inhibits axon regeneration in DRG cultures and in the sciatic nerve.\",\n      \"method\": \"Co-immunoprecipitation (Prom1–ALK4), Smad2 phosphorylation assays, Prom1 knockout mice, AAV-mediated overexpression in DRG neurons and in vivo sciatic nerve model, cholesterol assays, gene expression profiling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP binding partner identification, in vivo KO phenotype, in vivo and in vitro gain-of-function, mechanistic pathway dissection\",\n      \"pmids\": [\"32554499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD133 silencing by lentiviral shRNA in patient-derived GBM neurospheres impairs self-renewal and tumorigenic capacity; CD133 undergoes interconversion between cytoplasmic and plasma-membrane localizations in neurosphere cells (not a strict hierarchy between CD133+ and CD133− cells).\",\n      \"method\": \"Lentivirus-mediated shRNA knockdown, neurosphere self-renewal assays, xenograft tumor formation, immunofluorescence subcellular localization\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype, but single lab\",\n      \"pmids\": [\"23307586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD133 suppresses neuroblastoma cell differentiation (neurite extension and differentiation marker expression) and this suppression is mechanistically dependent on p38MAPK and PI3K/Akt pathways; CD133 suppresses RET tyrosine kinase transcription, and RET overexpression rescues CD133-mediated inhibition of neurite elongation, placing CD133 upstream of RET in a differentiation-regulatory axis.\",\n      \"method\": \"CD133 overexpression/knockdown in NB cell lines and primary tumor spheres, pathway inhibitor experiments (p38MAPK, PI3K/Akt), RET rescue experiments, gene expression analysis, colony formation and xenograft assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via rescue experiment, pathway inhibitors, defined phenotypic readouts; single lab\",\n      \"pmids\": [\"20818439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD133 expression increases IL-1β expression and its downstream chemokines CCL3, CXCL3, and CXCL5 in glioma cells, leading to increased neutrophil recruitment in vitro and in vivo; this places CD133 upstream of IL-1β signaling in modulation of the glioma tumor microenvironment.\",\n      \"method\": \"Forced CD133 expression in U87MG glioma cells, trans-well neutrophil recruitment assays, in vivo xenograft assays, gene expression analysis, correlation analysis in patient malignant glioma data\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with in vitro and in vivo functional readouts; single lab\",\n      \"pmids\": [\"28736425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD133 regulates RhoA and Rac1 GTPase activities to control microvesicle (MV) budding from the plasma membrane; EGF-induced NF-κB activation upregulates CD133 expression, which then modulates MV release; CD133-containing MVs from KRAS-mutant colon cancer cells deliver mutant KRAS to adjacent cells, activating KRAS downstream signaling and conferring chemoresistance to anti-EGFR drugs.\",\n      \"method\": \"siRNA knockdown and overexpression of CD133, nanoparticle tracking analysis of MV size and number, GTPase activity assays (RhoA, Rac1), KRAS oncoprotein transfer experiments, proliferation/motility assays with anti-EGFR drugs\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection with GTPase assays and functional transfer experiments; single lab\",\n      \"pmids\": [\"30521383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD133 transcription is controlled by both promoter CpG island methylation and histone modifications; CD133+ ovarian cancer cells maintain a hypomethylated promoter state, whereas CD133− progeny show increased promoter methylation; treatment with DNA methyltransferase and HDAC inhibitors synergistically restores CD133 surface expression in CD133− cells.\",\n      \"method\": \"Bisulfite sequencing, ChIP for histone marks, flow cytometry after epigenetic drug treatment, cell sorting, xenograft assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct epigenetic mechanism established with bisulfite sequencing and ChIP; single lab\",\n      \"pmids\": [\"18836486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Promoter CpG island DNA methylation heterogeneously controls CD133 expression within individual colon cancer and glioblastoma cell lines; differential histone modification marks (active vs. repressed) accompany DNA methylation changes; this promoter methylation signature is tumor-specific and absent from normal brain and colon.\",\n      \"method\": \"Bisulfite sequencing, ChIP for histone marks, FACS-sorted CD133+/− cell populations, comparative methylation analysis of tumors vs. normal tissue\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct epigenetic characterization with ChIP and bisulfite sequencing in sorted populations; single lab\",\n      \"pmids\": [\"18829568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DNA hypomethylation of the CD133 P1, P2, and P3 proximal promoters is an important determinant of CD133 expression in glioblastomas; P1 region (flanking exon 1A) shows highest promoter activity and is inactivated by in vitro methylation; treatment with 5-azacytidine and/or valproic acid restores CD133 mRNA in glioma cells.\",\n      \"method\": \"Bisulfite sequencing, promoter-reporter luciferase assays with in vitro methylation, 5-azacytidine and valproic acid treatments, RT-PCR\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter activity assays with direct methylation manipulation; single lab\",\n      \"pmids\": [\"18679414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD133 is associated with cholesterol-binding activity and is selectively concentrated in cholesterol-rich plasma membrane microdomains (lipid rafts) within membrane protrusions.\",\n      \"method\": \"Biochemical fractionation and cholesterol interaction studies described in review context, supported by prior experimental data in cited literature\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — review paper summarizing biochemical cholesterol-binding data without primary experimental detail in this paper\",\n      \"pmids\": [\"23161072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"An intronic 10 bp deletion in PROM1 intron 21 disrupts an SRSF2 splicing factor recognition site and causes complete exon 22 skipping in vitro, leading to a frameshift and premature termination codon, establishing intronic splicing mutations as a mechanism for PROM1 loss-of-function in cone-rod dystrophy.\",\n      \"method\": \"Minigene splicing reporter assay, bioinformatic SRSF2 binding site prediction, homozygosity mapping, direct sequencing\",\n      \"journal\": \"Molecular vision\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — functional splicing assay with minigene reconstitution; single lab but mechanistically definitive\",\n      \"pmids\": [\"26702251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A deep intronic variant in PROM1 intron 18 activates a pseudoexon through altered splicing, leading to a premature termination codon and functional null allele, causing autosomal recessive cone-rod dystrophy; this was confirmed by whole-genome sequencing and minigene splicing reporter assays.\",\n      \"method\": \"Whole-genome sequencing, minigene splicing reporter (in silico + in vitro functional analysis), homozygosity mapping\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — functional minigene splicing validation; single family/lab\",\n      \"pmids\": [\"26153215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The c.C1902G (p.Y634X) nonsense mutation in PROM1 results in a truncated, labile, and mislocalized protein as shown by confocal microscopy of transfected cells, while a splice-site mutation (c.C1682+3A>G) disrupts mRNA splicing as shown by bridge-PCR; both mutations underlie hereditary macular and rod-cone dystrophy.\",\n      \"method\": \"Whole exome sequencing, transient transfection of mutant PROM1 constructs in cultured cells, confocal microscopy for protein localization, bridge-PCR for splice analysis\",\n      \"journal\": \"Graefe's archive for clinical and experimental ophthalmology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional characterization of protein localization and splicing in cultured cells; single lab\",\n      \"pmids\": [\"30588538\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PROM1 (CD133/prominin-1) is a pentaspan transmembrane cholesterol-binding glycoprotein that localizes constitutively to plasma membrane protrusions (microvilli, filopodia) via interactions with gangliosides, PI3K, and the Arp2/3 complex (regulated by phosphorylation of Y828); in the cytoplasm it traffics via dynein/HDAC6 to pericentrosomal recycling endosomes where it sequesters GABARAP to inhibit autophagy initiation and suppress differentiation; it forms a complex with E-cadherin and β-catenin to promote Wnt/β-catenin signaling, interacts with ALK4 to drive Smad2 phosphorylation and cholesterol downregulation supporting axon regeneration, and modulates microvesicle release by regulating RhoA and Rac1 GTPase activity; its transcription is controlled by tissue-specific alternative promoters whose activity is regulated by CpG methylation (written/erased by DNMT/TET machinery) and histone modifications, with nucleolin acting as a direct transcriptional activator at the P1 promoter in hematopoietic stem cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PROM1 (CD133/prominin-1) is a pentaspan transmembrane glycoprotein that organizes plasma membrane protrusion architecture and integrates signaling pathways controlling stemness, differentiation, and autophagy. At the cell surface, PROM1 localizes constitutively to microvilli and filopodia via a phosphorylation-dependent (Y828) interaction with PI3K and the Arp2/3 complex, regulated by ganglioside binding, and forms a complex with E-cadherin and β-catenin to sustain Wnt/β-catenin signaling [PMID:30328220, PMID:29431914]; it also interacts with ALK4 to activate Smad2 phosphorylation, downregulate cholesterol, and promote axon regeneration [PMID:32554499], and modulates microvesicle release by regulating RhoA and Rac1 GTPase activities [PMID:30521383]. Intracellularly, PROM1 traffics via HDAC6 and dynein to pericentrosomal recycling endosomes where it sequesters GABARAP to inhibit autophagy initiation and suppress differentiation [PMID:30783186]. Loss-of-function mutations in PROM1, including nonsense, splice-site, and deep intronic variants, cause autosomal recessive cone-rod dystrophy and macular dystrophy [PMID:26702251, PMID:30588538].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing PROM1 as a pentaspan transmembrane glycoprotein with an intrinsic capacity to target plasma membrane protrusions (microvilli, filopodia) independently of cell type resolved where the protein resides and that its localization is cell-autonomous.\",\n      \"evidence\": \"Immunofluorescence, immunoprecipitation, and electron microscopy in Caco-2 cells and transfected fibroblasts\",\n      \"pmids\": [\"10681530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PROM1 is targeted to protrusions was unknown\", \"No interacting partners identified at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of the AC133-2 splice isoform and its selective expression on hematopoietic stem cells, with loss upon differentiation, established PROM1 as a stem-cell-associated marker with regulated alternative splicing.\",\n      \"evidence\": \"cDNA cloning, glycosylation analysis, RT-PCR across tissues, flow cytometry of HSCs, immunofluorescence of neonatal epidermis\",\n      \"pmids\": [\"12042327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of the 27-nt exon deletion was not determined\", \"Whether expression loss upon differentiation is transcriptional or post-transcriptional was unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Three independent studies converged to show that PROM1 transcription is controlled by CpG methylation of its alternative promoters (P1–P3) together with histone modifications, explaining the on/off switching of CD133 expression in tumors versus normal tissues and between sorted CD133+ and CD133− populations.\",\n      \"evidence\": \"Bisulfite sequencing, ChIP for histone marks, promoter-reporter assays with in vitro methylation, epigenetic drug treatments in ovarian cancer, glioblastoma, and colon cancer lines\",\n      \"pmids\": [\"18836486\", \"18829568\", \"18679414\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the DNMTs and demethylases responsible in vivo was not established\", \"Chromatin remodelers acting at PROM1 promoters were not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing that CD133 suppresses neuroblastoma differentiation through p38MAPK and PI3K/Akt pathways and represses RET transcription established a signaling axis through which PROM1 actively inhibits differentiation rather than merely marking undifferentiated cells.\",\n      \"evidence\": \"Overexpression/knockdown in neuroblastoma lines, pathway inhibitor epistasis, RET rescue experiments\",\n      \"pmids\": [\"20818439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical mechanism linking CD133 to p38MAPK and PI3K activation was not defined\", \"Whether RET repression is transcriptionally direct was not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that CD133 knockdown impairs glioblastoma neurosphere self-renewal and that CD133 dynamically interconverts between surface and cytoplasmic pools showed that PROM1 function involves regulated subcellular trafficking rather than a fixed surface identity.\",\n      \"evidence\": \"Lentiviral shRNA knockdown, neurosphere assays, xenograft formation, immunofluorescence localization\",\n      \"pmids\": [\"23307586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking machinery responsible for surface–cytoplasm interconversion was not identified\", \"Whether cytoplasmic CD133 has distinct signaling functions was unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Two studies identified deep intronic mutations in PROM1 that disrupt splicing (exon skipping and pseudoexon activation) to produce null alleles causing autosomal recessive cone-rod dystrophy, establishing PROM1 as essential for photoreceptor maintenance.\",\n      \"evidence\": \"Minigene splicing reporter assays, whole-genome sequencing, homozygosity mapping in affected families\",\n      \"pmids\": [\"26702251\", \"26153215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Photoreceptor-specific function of PROM1 protein was not mechanistically dissected\", \"Animal model validation of these specific splicing mutations was not performed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying nucleolin as a direct transcriptional activator of the PROM1 P1 promoter in HSPCs, with downstream elevation of active β-catenin and Akt, linked PROM1 transcription to a defined upstream regulator and explained its tissue-specific expression in the hematopoietic compartment.\",\n      \"evidence\": \"ChIP for nucleolin at P1 promoter, promoter-reporter assays, siRNA knockdown, colony-forming and LTC-IC assays in primary HSPCs\",\n      \"pmids\": [\"26183533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether nucleolin regulation of PROM1 occurs in non-hematopoietic tissues was not tested\", \"Other transcription factors cooperating with nucleolin at P1 were not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Dissecting how PROM1 shapes microvillar architecture through Y828 phosphorylation-dependent PI3K and Arp2/3 recruitment, with ganglioside binding providing an additional regulatory input, provided the first molecular mechanism for PROM1's constitutive protrusion targeting.\",\n      \"evidence\": \"High-resolution microscopy, co-IP with PI3K and Arp2/3, Y828 and ganglioside-binding-site mutagenesis in MDCK cells\",\n      \"pmids\": [\"30328220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the PROM1–ganglioside interaction was not resolved\", \"Kinase(s) responsible for Y828 phosphorylation were not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing that CD133 forms a complex with E-cadherin and β-catenin and that its loss reduces β-catenin levels and TCF/LEF activity established PROM1 as a permissive factor for canonical Wnt signaling and linked it to renal tubular repair after injury.\",\n      \"evidence\": \"Co-IP of CD133–E-cadherin–β-catenin, siRNA knockdown, TCF/LEF luciferase reporter, senescence assays in renal cells\",\n      \"pmids\": [\"29431914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PROM1 directly stabilizes β-catenin or acts indirectly through E-cadherin sequestration was not distinguished\", \"In vivo renal injury model with genetic PROM1 deletion was not performed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that CD133 regulates RhoA and Rac1 GTPase activities to control microvesicle budding, and that CD133-containing microvesicles transfer oncogenic KRAS to recipient cells, revealed a role for PROM1 in intercellular cargo transfer via extracellular vesicles.\",\n      \"evidence\": \"siRNA/overexpression of CD133, nanoparticle tracking, GTPase activity assays, functional KRAS transfer experiments in colon cancer cells\",\n      \"pmids\": [\"30521383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PROM1 modulates GTPase activity (direct GAP/GEF interaction vs. indirect) was not resolved\", \"In vivo relevance of PROM1-mediated microvesicle release was not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying the HDAC6/dynein-dependent trafficking of CD133 to pericentrosomal recycling endosomes, where it sequesters GABARAP to block ULK1 activation and autophagy initiation, provided a unified mechanism explaining how PROM1 suppresses both primary ciliogenesis and differentiation.\",\n      \"evidence\": \"Co-IP (CD133–HDAC6, CD133–GABARAP), confocal imaging, dynein inhibition, Src kinase manipulation, ULK1 phosphorylation assays\",\n      \"pmids\": [\"30783186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and direct vs. bridged nature of the CD133–GABARAP interaction were not determined\", \"Whether autophagy suppression fully accounts for PROM1's anti-differentiation activity was not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that PROM1 interacts with ALK4 to synergistically activate Smad2 and downregulate cholesterol metabolism, promoting axon regeneration in vivo, extended PROM1's signaling repertoire to TGF-β/Smad signaling and neuronal repair.\",\n      \"evidence\": \"Co-IP (Prom1–ALK4), Prom1 knockout mice, AAV-mediated overexpression in DRG neurons and sciatic nerve model, cholesterol assays\",\n      \"pmids\": [\"32554499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PROM1 acts as a co-receptor or modulator of ALK4 kinase activity was not distinguished\", \"Role of cholesterol reduction versus other Smad2 targets in regeneration was not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the structural basis of PROM1's cholesterol and ganglioside binding, the identity of kinases phosphorylating Y828, whether the autophagy-suppressive and Wnt-stabilizing functions operate in the same or distinct cellular contexts, and how PROM1 loss specifically causes photoreceptor degeneration at the cellular level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of PROM1\", \"Kinase for Y828 phosphorylation unidentified\", \"Photoreceptor-specific mechanism of PROM1 function not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [14, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 11, 12, 13]}\n    ],\n    \"complexes\": [\n      \"E-cadherin–β-catenin complex\"\n    ],\n    \"partners\": [\n      \"CDH1\",\n      \"CTNNB1\",\n      \"HDAC6\",\n      \"GABARAP\",\n      \"ACVR1B\",\n      \"NCL\",\n      \"PIK3CA\",\n      \"ACTR2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}