{"gene":"NUMB","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1995,"finding":"Numb protein localizes asymmetrically during cell division and segregates into one daughter cell, where it is required for specification of correct cell fate. Its localization is coupled to mitosis, correlated with centrosome position, and is independent of microtubules and actin.","method":"Genetic loss-of-function, cytochalasin D treatment, nocodazole treatment, immunolocalization in Drosophila neuroblasts","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments with functional consequence, replicated across multiple labs subsequently","pmids":["7566172"],"is_preprint":false},{"year":2000,"finding":"Numb is an endocytic protein that localizes to endocytic organelles, is co-trafficked with internalizing receptors, and associates with the appendage domain of alpha-adaptin (a subunit of AP2/clathrin-coated pits). Dominant-negative Numb fragments inhibit both constitutive and ligand-regulated receptor-mediated internalization.","method":"Subcellular fractionation, co-immunoprecipitation with alpha-adaptin, dominant-negative overexpression, receptor internalization assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, dominant-negative functional assay, multiple orthogonal methods in one study","pmids":["11121447"],"is_preprint":false},{"year":2002,"finding":"In Drosophila sensory organ precursor cells, Numb acts by polarizing the distribution of alpha-Adaptin (required for receptor-mediated endocytosis). Alpha-Adaptin binds to Numb and localizes asymmetrically in a Numb-dependent fashion. Mutant alpha-Adaptin unable to bind Numb fails to localize asymmetrically and causes numb-like fate defects. Numb also binds the intracellular domain of Notch.","method":"Co-immunoprecipitation, genetic loss-of-function, binding-deficient mutant analysis, asymmetric division assay in Drosophila SOPs","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus mutagenesis plus genetic epistasis, replicated in multiple contexts","pmids":["12194853"],"is_preprint":false},{"year":2003,"finding":"Mammalian Numb promotes ubiquitination of membrane-bound Notch1 receptor via its PTB domain, resulting in degradation of the Notch1 intracellular domain and loss of Notch-dependent transcriptional activation. Numb interacts with the HECT domain E3 ligase Itch, and Numb and Itch act cooperatively to ubiquitinate membrane-tethered Notch1.","method":"Co-immunoprecipitation, ubiquitination assay, Hes1-luciferase reporter assay, PTB domain mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro ubiquitination assay, Co-IP, reporter assay with domain mutant, single lab with multiple orthogonal methods","pmids":["12682059"],"is_preprint":false},{"year":2003,"finding":"Human Numb is a substrate of MDM2 ubiquitin ligase; recombinant hNumb binds MDM2 in vitro and is ubiquitinated by MDM2 in an E1/E2/MDM2-dependent manner requiring the RING-finger domain. Co-transfection of hNumb and MDM2 in U2OS cells leads to Numb ubiquitination and degradation.","method":"In vitro ubiquitination assay with recombinant proteins, co-immunoprecipitation, co-transfection with RING-finger mutant MDM2","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted ubiquitination assay plus active-site mutagenesis plus cell-based confirmation, single lab","pmids":["12646252"],"is_preprint":false},{"year":2003,"finding":"CRMP-2 interacts with Numb, and the CRMP-2/Numb complex localizes to axonal growth cones where Numb associates with L1 (a neuronal adhesion molecule undergoing endocytosis). Dominant-negative CRMP-2 or CRMP-2 siRNA inhibits endocytosis of L1 at growth cones and suppresses axon growth.","method":"Co-immunoprecipitation, colocalization by immunofluorescence, dominant-negative overexpression, siRNA knockdown, L1 endocytosis assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, siRNA and dominant-negative with defined functional readout, multiple orthogonal methods","pmids":["12942088"],"is_preprint":false},{"year":2005,"finding":"In Drosophila SOP cells, Numb induces endocytosis of Sanpodo (a four-pass transmembrane protein that enables Notch signaling) via alpha-Adaptin-dependent clathrin-mediated endocytosis. Numb binds Sanpodo through its PTB domain. In numb or alpha-adaptin mutants, Sanpodo is not endocytosed. Numb regulates this endocytosis throughout the cell cycle, not only after division.","method":"Genetic loss-of-function (numb, alpha-adaptin mutants), co-localization with Rab5/Rab7 endosomal markers, PTB domain binding assay, Drosophila SOP imaging","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis plus binding domain analysis plus endosomal colocalization, replicated across multiple genetic backgrounds","pmids":["16113648"],"is_preprint":false},{"year":2007,"finding":"Numb is an endocytic adaptor required for directional integrin endocytosis during cell migration. Numb binds integrin-beta subunits and localizes to clathrin-coated structures at the leading edge. RNAi knockdown of Numb impairs integrin endocytosis and directional cell migration. aPKC phosphorylates Numb, releasing it from clathrin-coated structures and preventing integrin binding. Numb interacts with the aPKC-binding partner PAR-3.","method":"RNAi knockdown, co-immunoprecipitation, live-cell and fixed immunofluorescence, integrin endocytosis assay, phosphorylation assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNAi with defined cellular phenotype, Co-IP, phosphorylation assay, multiple orthogonal methods","pmids":["17609107"],"is_preprint":false},{"year":2008,"finding":"NUMB enters a tricomplex with p53 and the E3 ubiquitin ligase HDM2/MDM2, thereby preventing ubiquitination and degradation of p53. This results in increased p53 protein levels and activity, and regulation of p53-dependent phenotypes. The PTB domain of NUMB is required for this function.","method":"Co-immunoprecipitation (tricomplex), ubiquitination assay, p53 stability/activity assays, domain mapping, breast cancer cell lines","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP of tricomplex, ubiquitination assay, multiple cancer cell lines, replicated in primary tumor cells","pmids":["18172499"],"is_preprint":false},{"year":2009,"finding":"Mammalian Notch1 is constitutively internalized and trafficked to recycling and late endosomal compartments. Numb overexpression promotes sorting of Notch1 to late endosomes for degradation; Numb depletion facilitates Notch1 recycling. Numb mutants lacking Itch interaction or endocytic protein-binding motifs fail to promote Notch1 degradation.","method":"Fluorescence microscopy of endosomal trafficking, Numb knockdown/overexpression, Numb mutant analysis, co-immunoprecipitation with Itch","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — live trafficking assay, loss-of-function, domain mutants with defined trafficking readout, single lab with multiple orthogonal methods","pmids":["19567869"],"is_preprint":false},{"year":2009,"finding":"Numb interacts with E-cadherin through its PTB domain and regulates E-cadherin localization at lateral cell-cell junctions. Numb also binds Par3 in polarized MDCK cells. After Src activation or HGF treatment, Numb dissociates from E-cadherin/Par3 and associates preferentially with aPKC-Par6, sequestering aPKC in the cytosol. Numb knockdown causes basolateral-to-apicolateral E-cadherin translocation, elevated actin polymerization, decreased cell-cell adhesion, and increased migration.","method":"Co-immunoprecipitation, shRNA knockdown, confocal microscopy, cell scattering assay, E-cadherin localization","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, shRNA with defined polarity/adhesion phenotype, multiple orthogonal methods, single lab","pmids":["19609305"],"is_preprint":false},{"year":2011,"finding":"Numb directly interacts with p120 catenin (which is bound to E-cadherin and prevents its internalization). Numb accumulates at intercellular adhesion sites; its depletion impairs E-cadherin internalization while p120 depletion accelerates it. aPKC phosphorylates Numb and inhibits its association with p120 and alpha-adaptin, thereby attenuating E-cadherin endocytosis. A phosphomimetic Numb mutant or an alpha-adaptin-binding-deficient mutant fails to restore E-cadherin internalization.","method":"Co-immunoprecipitation, RNAi depletion, phosphomimetic/binding-deficient mutant analysis, E-cadherin internalization assay, aPKC kinase assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay plus Co-IP plus mutagenesis plus internalization assay with multiple controls, single lab","pmids":["21775625"],"is_preprint":false},{"year":2012,"finding":"MDM2 uses a dual-site mechanism (N-terminal hydrophobic pocket and acidic domain) to bind and ubiquitinate NUMB, analogous to its interaction with p53. Only one region within the PTB domain of NUMB (amino acids 113–148) mediates binding to both MDM2 domains. By binding to both MDM2 domains, NUMB disrupts the MDM2-p53 complex and inhibits MDM2-catalyzed ubiquitination of p53.","method":"In vitro binding assays, ubiquitination assay, domain deletion and point-mutant analysis, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted ubiquitination assay plus domain mutagenesis, mechanistically detailed, single lab","pmids":["22337874"],"is_preprint":false},{"year":2012,"finding":"Numb knockdown causes G2/M arrest and reduced cell growth in melanoma cells. Numb co-immunoprecipitates with and colocalizes with polo-like kinase Plk1; Numb cycles in a cell-cycle-dependent manner with Plk1. Numb expression is required for Plk1 protein stability and proper localization to spindle poles during mitosis. Numb reduction leads to mislocalized Plk1 and disorganized gamma-tubulin at centrosomes.","method":"Co-immunoprecipitation, colocalization, siRNA knockdown, cell cycle analysis, immunofluorescence of spindle poles","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and colocalization with defined cellular phenotype, single lab, single set of methods","pmids":["22593191"],"is_preprint":false},{"year":2011,"finding":"All four Numb isoforms negatively regulate Notch1 in transcription and myogenic differentiation assays. Notch3 is not polyubiquitinated nor degraded when co-expressed with Numb. Unlike Notch1, Notch3 is not a target of Numb-mediated ubiquitination, demonstrating receptor-specific regulation.","method":"Transcription reporter assay, myogenic differentiation assay, ubiquitination assay with co-expressed proteins","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional assay plus ubiquitination assay, single lab, limited replication","pmids":["21356309"],"is_preprint":false},{"year":2013,"finding":"In cardiac development, NUMB and NUMBL are required for downregulation of ERBB2 signaling by promoting ERBB2 transition from early to late endosomes for degradation via interaction with the small GTPase Rab7. Loss of NUMB/NUMBL causes a partial block of late endosome formation, sustained ERBB2/STAT5 signaling, YAP1 nuclear localization, and aberrant cardiomyocyte proliferation resulting in ventricular noncompaction.","method":"Cardiac-specific double knockout, endosomal fractionation, co-immunoprecipitation with Rab7, rescue by heterozygous ERBB2 or YAP1 loss-of-function","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular phenotype, Co-IP with Rab7, genetic rescue experiments, multiple orthogonal methods","pmids":["28067668"],"is_preprint":false},{"year":2018,"finding":"Numb PTB domain, using two distinct binding surfaces, recognizes repeating motifs within Pon in a multivalent manner. This multivalent Numb-Pon interaction leads to liquid-liquid phase separation of the complex, forming basal condensates in Drosophila neuroblasts. Perturbation of this phase transition impairs basal localization of Numb and subsequent suppression of Notch signaling during asymmetric neuroblast division.","method":"Crystal structure/structural analysis of PTB-Pon interaction, in vitro phase separation assay, mutagenesis of binding surfaces, Drosophila live imaging of Numb localization","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural analysis plus in vitro reconstitution of phase separation plus mutagenesis plus in vivo functional validation, single lab","pmids":["29467404"],"is_preprint":false},{"year":2018,"finding":"Numb depletion from proximal tubules promotes mitochondrial fragmentation by increasing phosphorylation of Drp1 at Ser637 (mouse Ser656), which recruits Drp1 to mitochondria. ROCK kinase inhibition (Y-27632) attenuates Drp1 phosphorylation and fragmentation in Numb-deficient cells. Drp1 inhibitor mdivi-1 restores mitochondrial morphology in Numb-KO mice.","method":"Proximal tubule-specific Numb KO mice, phospho-Drp1 western blot, ROCK inhibitor treatment, Drp1 inhibitor rescue, electron microscopy","journal":"Antioxidants & redox signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined mitochondrial phenotype plus pharmacological rescue, single lab","pmids":["29890853"],"is_preprint":false},{"year":2017,"finding":"NUMB and NUMBL interact with VEGFR2 and VEGFR3, controlling VEGF receptor endocytosis, signaling activation, and recycling back to the plasma membrane. Inducible endothelial-specific inactivation of Numb/Numbl impairs vessel growth, reduces endothelial proliferation/sprouting, and decreases VEGF receptor activation.","method":"Co-immunoprecipitation with VEGFR2/3, inducible endothelial-specific KO mice, receptor recycling assay, retinal angiogenesis imaging","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus conditional KO with defined angiogenic phenotype, multiple orthogonal methods, single lab","pmids":["26069237"],"is_preprint":false},{"year":2017,"finding":"Plk1 phosphorylates Numb, leading to enhanced proteasomal degradation of Numb and impaired Numb/p53 pathway. Cells carrying the unphosphorylated form of Numb are more sensitive to doxorubicin. This identifies a mechanism by which Plk1 antagonizes p53 during DNA damage response via Numb destabilization.","method":"In vitro Plk1 kinase assay, proteasome inhibitor experiments, phosphomimetic/unphosphorylatable Numb mutants, doxorubicin sensitivity assay, xenograft mouse model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay plus mutagenesis plus cell-based and in vivo validation, single lab with multiple orthogonal methods","pmids":["29059161"],"is_preprint":false},{"year":2018,"finding":"NUMB binds directly to the ARF6 guanine nucleotide exchange factor EFA6B through its PTB domain (recognizing an N-terminal NPLF motif) and promotes EFA6B exchange activity in vitro. A NUMB-EFA6B-ARF6 axis regulates recycling of RAC1 and is critical for formation of circular dorsal ruffles and acquisition of mesenchymal migration. Loss of NUMB promotes HGF-induced cell migration and invasion.","method":"Co-immunoprecipitation, in vitro GEF activity assay, PTB domain mutant analysis, RNAi knockdown, cell migration/invasion assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro GEF assay plus Co-IP plus domain mutagenesis plus functional migration assay, multiple orthogonal methods, single lab","pmids":["30061108"],"is_preprint":false},{"year":2020,"finding":"NUMB stabilizes the NOTCH1 intracellular domain (N1ICD) by recruiting the deubiquitinase BAP1 to N1ICD, facilitating the BAP1-BRCA1 complex interaction with N1ICD to reduce its ubiquitination. This stabilization is independent of NUMB's role in endocytosis. BAP1 stabilizes N1ICD independent of its DUB catalytic activity but relying on its BRCA1-inhibiting function.","method":"Co-immunoprecipitation, ubiquitination assay, BAP1 catalytic mutant analysis, N1ICD stability assay, cortical neural progenitor cell assay","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ubiquitination assay with mutant analysis, single lab, contradicts canonical Notch-inhibitory role of NUMB","pmids":["31504682"],"is_preprint":false},{"year":2023,"finding":"Numb binds Parkin and facilitates Parkin-mediated mitophagy (mitochondrial quality control). Deficiency in the Numb/Parkin pathway in prostate or lung adenocarcinomas causes metabolic reprogramming with increased lactate production, upregulation of histone lactylation, and transcription of neuroendocrine-associated genes driving cell fate transition.","method":"Co-immunoprecipitation (Numb-Parkin binding), mitophagy assay, Numb KO cell lines, metabolomics, histone lactylation measurement","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP for Numb-Parkin interaction plus KO phenotype with metabolic readouts, single lab","pmids":["36724072"],"is_preprint":false},{"year":2024,"finding":"Numb localizes to the ciliary pocket and acts as an endocytic adaptor to incorporate Ptch1 into clathrin-coated vesicles, promoting Ptch1 exit from the cilium. Loss of Numb impedes Shh-induced Ptch1 exit from the cilium, reduces Hedgehog signaling, impairs Shh-induced neural progenitor differentiation, and reduces cerebellar granule cell precursor proliferation in vivo.","method":"Proximity labeling and quantitative proteomics (ciliary Numb identification), live imaging of Ptch1 ciliary exit, Numb conditional KO in cerebellum, neural progenitor differentiation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — proximity proteomics plus live imaging plus conditional KO with multiple cellular phenotypes, multiple orthogonal methods","pmids":["38664376"],"is_preprint":false},{"year":2023,"finding":"High cell density induces phosphorylation of SPTAN1 (spectrin alpha), which recruits NUMB isoforms 1 and 2 (long PTB-containing isoforms) to the plasma membrane. NUMB then sequesters MARK kinases at the membrane, rendering them inaccessible for phosphorylation and inhibition of Hippo kinases MST1/2, thereby activating Hippo signaling and blocking YAP activity for cell contact inhibition. Low cell density leads to SPTAN1 dephosphorylation and NUMB cytoplasmic relocation, releasing MARKs to inhibit MST1/2 and activate YAP.","method":"Co-immunoprecipitation (NUMB-SPTAN1, NUMB-MARK), NUMB isoform-specific KO, liver-specific double KO (NUMB/WW45), phospho-SPTAN1 assays, Hippo kinase activity assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, KO phenotype with tumorigenesis readout, kinase activity assay, isoform specificity established, single lab with multiple orthogonal methods","pmids":["37843276"],"is_preprint":false},{"year":2003,"finding":"A novel transmembrane protein NIP (Numb-interacting protein) contains NXXF motifs that bind the PTB domain of Numb. Expression of NIP in COS-7 cells recruits Numb from cytosol to plasma membrane in a NXXF-dependent manner. RNAi knockdown of NIP in Drosophila S2 cells releases Numb to the cytosol. In dividing Drosophila neuroblasts, NIP colocalizes with Numb in a basal cortical crescent.","method":"Co-immunoprecipitation, RNAi knockdown, membrane recruitment assay, immunofluorescence in Drosophila neuroblasts","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP, RNAi, and localization data, single lab, mechanistically informative for plasma membrane targeting","pmids":["14670962"],"is_preprint":false},{"year":2006,"finding":"LNX1 (Ligand-of-Numb protein X1) provides an endocytic scaffold for JAM4; LNX1 facilitates endocytosis of JAM4, and Numb is necessary for LNX1-mediated JAM4 endocytosis. JAM4, LNX1, and Numb form a tripartite complex in vitro. LNX1 is involved in TGF-beta-induced redistribution of JAM4.","method":"Yeast two-hybrid, co-immunoprecipitation from kidney lysates, in vitro tripartite complex reconstitution, dominant-negative and RNAi experiments, endocytosis assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro complex reconstitution plus RNAi plus Co-IP from tissue, single lab","pmids":["16832352"],"is_preprint":false},{"year":2016,"finding":"Numb directly interacts with VEGFR2 and VEGFR3 and controls their endocytosis and recycling. Numb proteins counteract VEGF receptor degradation and promote VEGFR2 recycling to the plasma membrane, sustaining VEGF receptor activation in response to ligand.","method":"Co-immunoprecipitation, receptor recycling/degradation assay, Numb/Numbl inducible endothelial KO, VEGF signaling assays","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, receptor trafficking assay, conditional KO with angiogenic phenotype, multiple orthogonal methods","pmids":["26069237"],"is_preprint":false},{"year":1999,"finding":"Genetic epistasis in Drosophila CNS shows that both Notch and Numb function downstream of cell division genes (cyclinA, rca1, string/cdc25). In the absence of cell cycle entry into metaphase, Numb protein prevents Notch signaling from specifying sib fate; progression through the cell cycle is required for asymmetric localization of Numb.","method":"Genetic epistasis using loss-of-function mutations in cyclinA, rca1, stg, numb, Notch; double-mutant analysis; nocodazole treatment","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multi-gene epistasis with double and triple mutants, well-controlled genetic study","pmids":["10331986"],"is_preprint":false},{"year":2022,"finding":"Numb regulates intracellular Tau levels; conditional inactivation of Numb in retinal ganglion cells increases Tau levels and leads to axonal blebbing and neuronal loss. In the TauP301S tauopathy model, conditional Numb inactivation accelerates neurodegeneration. Overexpression of the long Numb isoform (Numb-72) decreases intracellular Tau levels and reduces axonal blebbing.","method":"Conditional KO of Numb in RGCs and spinal motoneurons, TauP301S cross, Tau level quantification by western blot, axonal blebbing assay, behavioral test, electrophysiology of cultured neurons","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO plus gain-of-function with multiple cellular and in vivo phenotypes, single lab with orthogonal methods","pmids":["36260685"],"is_preprint":false},{"year":2016,"finding":"The splicing factors ASF/SF2 and PTBP1 regulate alternative splicing of Numb exon 9 (E9). Activation of the MAPK/ERK pathway promotes E9 inclusion (producing p72/p71 isoforms) in cancer cells, switching Numb isoform expression from E9-excluded (differentiated cell) to E9-included (progenitor) forms.","method":"Splicing reporter assay, siRNA knockdown of splicing factors, MEK/ERK inhibitor and activator treatment, RT-PCR isoform analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — splicing reporter assay plus RNAi plus pharmacological pathway manipulation, single lab","pmids":["27041567"],"is_preprint":false},{"year":2015,"finding":"Numb is required for preventing p53-dependent senescence in skeletal muscle stem cells following injury. In Numb-deficient satellite cells, senescence is rescued to wild-type levels by antioxidant treatment or p53 ablation, establishing that Numb acts upstream of p53 to prevent oxidative stress-induced senescence.","method":"Conditional Numb KO in muscle satellite cells, antioxidant treatment rescue, p53 genetic ablation rescue, senescence assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined senescence phenotype plus genetic rescue (p53 ablation) plus pharmacological rescue, multiple orthogonal methods","pmids":["26503169"],"is_preprint":false},{"year":2010,"finding":"Numb depletion in MDCK cells destabilizes E-cadherin-based cell-cell adhesion and promotes loss of epithelial cell morphology. Numb knockdown potentiates HGF-induced lamellipodia formation and cell dispersal via hyperactivation of Rac1-GTP. Rac1 inhibition in Numb-depleted cells stabilizes cell-cell contacts, establishing that Numb acts to suppress Rac1-GTP accumulation.","method":"shRNA knockdown, Rac1-GTP pull-down assay, Rac1 inhibitor rescue, HGF-stimulated cell scattering assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RNAi with defined cellular phenotype and Rac1-GTP biochemical readout, single lab","pmids":["21147098"],"is_preprint":false}],"current_model":"NUMB is a multi-functional endocytic adaptor protein that asymmetrically segregates at cell division to act as a cell fate determinant; it inhibits Notch signaling by recruiting the E3 ligase Itch to ubiquitinate membrane Notch1 and by directing post-endocytic sorting of Notch1 to late endosomes for degradation, while simultaneously protecting p53 from MDM2-mediated ubiquitination by forming a tricomplex with p53 and MDM2; it controls directional trafficking of integrins, E-cadherin, VEGF receptors, and Ptch1 via clathrin/AP2-dependent endocytosis, regulated by aPKC phosphorylation; it undergoes liquid-liquid phase separation with its basal cortical partner Pon; it suppresses Rac1 and RhoA/ROCK-mediated migration; it facilitates Parkin-mediated mitophagy; and it senses cell density by binding phospho-SPTAN1 to activate Hippo/MST1/2 signaling and suppress YAP."},"narrative":{"mechanistic_narrative":"NUMB is a multifunctional endocytic adaptor and cell-fate determinant that segregates asymmetrically during mitosis to specify daughter-cell identity, a process coupled to cell-cycle progression and centrosome position but independent of microtubules and actin [PMID:7566172, PMID:10331986]. Its membrane-proximal localization in dividing cells is achieved through multivalent PTB-domain engagement of cortical partners: in Drosophila neuroblasts NUMB recognizes repeating motifs in Pon to drive liquid-liquid phase separation into basal condensates required for Notch suppression [PMID:29467404], and is recruited to the cortex by the transmembrane protein NIP [PMID:14670962]. Mechanistically NUMB functions as an endocytic adaptor that binds the alpha-adaptin appendage of the AP2/clathrin machinery to drive receptor-mediated internalization and post-endocytic sorting [PMID:11121447, PMID:12194853]. Through its PTB domain it engages numerous transmembrane cargoes and routes them to defined endosomal fates—it promotes Itch-dependent ubiquitination and late-endosomal degradation of Notch1 [PMID:12682059, PMID:19567869], directs Sanpodo endocytosis [PMID:16113648], and channels ERBB2 from early to late endosomes via Rab7 for degradation [PMID:28067668], while conversely sustaining VEGFR2/3 by promoting their recycling to the plasma membrane [PMID:26069237]. This adaptor activity is switched off by aPKC phosphorylation, which releases NUMB from clathrin structures and abolishes integrin and E-cadherin/p120-catenin binding, coupling NUMB-dependent trafficking to cell polarity and directional migration [PMID:17609107, PMID:21775625]. NUMB additionally stabilizes p53 by entering a tricomplex with p53 and the E3 ligase MDM2, occupying both MDM2 substrate-binding surfaces to block p53 ubiquitination—itself being an MDM2 substrate—thereby restraining oxidative-stress-induced senescence [PMID:12646252, PMID:18172499, PMID:22337874, PMID:26503169]. Plk1 phosphorylates NUMB to trigger its proteasomal degradation, antagonizing the NUMB-p53 axis during DNA damage [PMID:29059161]. Beyond these core roles NUMB suppresses Rac1/RhoA-driven migration [PMID:30061108, PMID:21147098], facilitates Parkin-mediated mitophagy [PMID:36724072], removes Ptch1 from the ciliary pocket to support Hedgehog signaling [PMID:38664376], and senses cell density via phospho-SPTAN1 to sequester MARK kinases and activate Hippo/MST1-2 signaling to restrain YAP [PMID:37843276].","teleology":[{"year":1995,"claim":"Established that Numb is a cell-fate determinant by showing it asymmetrically segregates into one daughter cell at division, linking a molecular asymmetry to a developmental decision.","evidence":"Genetic loss-of-function and immunolocalization in Drosophila neuroblasts with cytoskeletal drug treatments","pmids":["7566172"],"confidence":"High","gaps":["Molecular mechanism establishing the asymmetric cortical crescent not defined","Downstream effector of fate specification not identified at this stage"]},{"year":1999,"claim":"Placed Numb and Notch genetically downstream of cell-cycle genes, showing that mitotic progression is required for Numb asymmetric localization and Notch inhibition.","evidence":"Multi-gene genetic epistasis (cyclinA, rca1, stg, numb, Notch) in Drosophila CNS","pmids":["10331986"],"confidence":"High","gaps":["Biochemical coupling between cell-cycle machinery and Numb localization not resolved"]},{"year":2000,"claim":"Identified Numb as an endocytic adaptor by demonstrating it binds the alpha-adaptin AP2 appendage and is required for receptor internalization, providing a molecular activity underlying fate determination.","evidence":"Subcellular fractionation, alpha-adaptin Co-IP, and dominant-negative receptor internalization assays","pmids":["11121447"],"confidence":"High","gaps":["Specific cargoes endocytosed in vivo not yet defined","Connection of endocytosis to Notch inhibition not yet established"]},{"year":2002,"claim":"Connected Numb's endocytic and fate-determining roles by showing Numb polarizes alpha-Adaptin distribution and binds the Notch intracellular domain, with alpha-Adaptin binding required for asymmetric localization.","evidence":"Co-IP, binding-deficient mutant analysis, and genetic epistasis in Drosophila SOPs","pmids":["12194853"],"confidence":"High","gaps":["Mechanism by which endocytosis suppresses Notch signaling not yet biochemically defined"]},{"year":2003,"claim":"Defined a biochemical mechanism of Notch inhibition: Numb recruits the HECT E3 ligase Itch via its PTB domain to ubiquitinate and degrade membrane Notch1, abolishing Notch transcriptional output.","evidence":"Co-IP, in vitro ubiquitination assay, Hes1-luciferase reporter, PTB-mutant analysis in mammalian cells","pmids":["12682059"],"confidence":"High","gaps":["Endosomal compartment of degradation not yet defined","Receptor specificity beyond Notch1 untested"]},{"year":2003,"claim":"Revealed reciprocal regulation by identifying Numb as an MDM2 substrate, and uncovered new endocytic cargoes (L1 via CRMP-2; NIP-mediated membrane recruitment), broadening Numb's adaptor repertoire.","evidence":"In vitro reconstituted ubiquitination with RING mutants; CRMP-2/L1 Co-IP and endocytosis assays; NIP membrane-recruitment and RNAi assays","pmids":["12646252","12942088","14670962"],"confidence":"High","gaps":["Functional consequence of MDM2-mediated Numb turnover unclear at this stage","NIP interaction confidence medium (single lab)"]},{"year":2005,"claim":"Showed that Numb regulates cargo endocytosis (Sanpodo) throughout the cell cycle via alpha-Adaptin-dependent clathrin endocytosis, extending its adaptor role beyond post-division fate specification.","evidence":"Genetic loss-of-function, Rab5/Rab7 colocalization, PTB-binding assays in Drosophila SOPs","pmids":["16113648"],"confidence":"High","gaps":["Direct link from Sanpodo endocytosis to Notch activation state incompletely mapped"]},{"year":2006,"claim":"Extended Numb adaptor function to LNX1-scaffolded JAM4 endocytosis, defining a tripartite complex and a role in junctional protein trafficking.","evidence":"Yeast two-hybrid, Co-IP from kidney lysates, in vitro tripartite reconstitution, RNAi endocytosis assay","pmids":["16832352"],"confidence":"Medium","gaps":["Physiological context of JAM4 regulation by Numb single-lab only"]},{"year":2007,"claim":"Demonstrated that aPKC phosphorylation acts as a molecular switch releasing Numb from clathrin structures, coupling Numb-dependent integrin endocytosis to polarized directional migration.","evidence":"RNAi, Co-IP, phosphorylation assay, integrin endocytosis and migration assays","pmids":["17609107"],"confidence":"High","gaps":["aPKC phosphosites on Numb not mapped here","Generality of the switch to other cargoes not yet tested"]},{"year":2008,"claim":"Established a tumor-suppressive role by showing NUMB forms a tricomplex with p53 and MDM2 to protect p53 from degradation, linking the adaptor to genome-stability signaling.","evidence":"Tricomplex Co-IP, ubiquitination and p53 stability assays, domain mapping in breast cancer cells","pmids":["18172499"],"confidence":"High","gaps":["Structural basis of tricomplex formation not yet resolved","Relationship to Numb's endocytic role unclear"]},{"year":2009,"claim":"Defined post-endocytic sorting as the route of Notch1 degradation, showing Numb directs Notch1 to late endosomes whereas its depletion favors recycling, dependent on Itch and endocytic motifs.","evidence":"Endosomal trafficking microscopy, Numb gain/loss-of-function, domain mutants, Itch Co-IP","pmids":["19567869"],"confidence":"High","gaps":["Sorting machinery directing late-endosomal targeting not fully identified"]},{"year":2009,"claim":"Linked Numb to epithelial integrity by showing it binds E-cadherin and Par3, and that an aPKC/Par6 switch redirects Numb to control junction stability and migration.","evidence":"Co-IP, shRNA, confocal microscopy, scattering assays in MDCK cells","pmids":["19609305"],"confidence":"High","gaps":["In vivo relevance of E-cadherin regulation not addressed"]},{"year":2010,"claim":"Showed Numb suppresses Rac1-GTP accumulation to maintain E-cadherin junctions and limit HGF-induced scattering, establishing a link to small-GTPase-driven motility.","evidence":"shRNA, Rac1-GTP pull-down, Rac1-inhibitor rescue, scattering assay","pmids":["21147098"],"confidence":"Medium","gaps":["Direct molecular connection between Numb and Rac1 regulation not defined here (single lab)"]},{"year":2011,"claim":"Detailed how aPKC phosphorylation inhibits Numb binding to p120-catenin and alpha-adaptin to attenuate E-cadherin endocytosis, and showed receptor-specific Notch regulation (Notch1 but not Notch3).","evidence":"Co-IP, RNAi, phosphomimetic/binding-deficient mutants, kinase and internalization assays; reporter and ubiquitination assays for Notch isoforms","pmids":["21775625","21356309"],"confidence":"High","gaps":["Structural basis of Notch receptor selectivity not resolved","Notch3 finding medium-confidence single-lab"]},{"year":2012,"claim":"Provided the mechanistic basis of p53 protection by showing NUMB occupies both MDM2 substrate-binding surfaces via a single PTB region, disrupting MDM2-p53 and inhibiting p53 ubiquitination.","evidence":"In vitro binding, ubiquitination, domain deletion and point mutants, Co-IP","pmids":["22337874"],"confidence":"High","gaps":["Stoichiometry and structure of the assembled tricomplex not determined"]},{"year":2012,"claim":"Implicated Numb in mitotic fidelity by showing it cycles with and stabilizes Plk1 for proper spindle-pole localization, with loss causing G2/M arrest.","evidence":"Co-IP, colocalization, siRNA, cell-cycle and spindle-pole immunofluorescence in melanoma cells","pmids":["22593191"],"confidence":"Medium","gaps":["Direct vs indirect effect on Plk1 stability not resolved","Single-lab, single set of methods"]},{"year":2015,"claim":"Established that Numb prevents p53-dependent oxidative-stress senescence in muscle stem cells, placing Numb genetically upstream of p53 in tissue regeneration.","evidence":"Conditional Numb KO, antioxidant and p53-ablation rescue, senescence assays","pmids":["26503169"],"confidence":"High","gaps":["Molecular link between Numb loss and oxidative stress not fully defined"]},{"year":2016,"claim":"Expanded Numb cargo control to VEGF receptors, showing it sustains VEGFR2/3 by promoting recycling, and identified MAPK/ERK-driven alternative splicing as a regulator of Numb isoform identity.","evidence":"Co-IP, recycling/degradation assays, endothelial inducible KO; splicing reporter, splicing-factor RNAi, ERK pathway manipulation","pmids":["26069237","27041567"],"confidence":"High","gaps":["Determinants choosing degradation (ERBB2/Notch) vs recycling (VEGFR) fate unclear","Splicing finding medium-confidence single-lab"]},{"year":2017,"claim":"Showed in vivo that NUMB/NUMBL route ERBB2 to Rab7-dependent late-endosomal degradation to restrain proliferation, and that Plk1 phosphorylates Numb to trigger its degradation and antagonize p53 during DNA damage.","evidence":"Cardiac double KO, endosomal fractionation, Rab7 Co-IP, genetic rescue; in vitro Plk1 kinase assay, phospho-mutants, doxorubicin sensitivity and xenografts","pmids":["28067668","29059161"],"confidence":"High","gaps":["Integration of ERBB2/YAP axis with Numb's other Hippo functions not addressed"]},{"year":2018,"claim":"Resolved the biophysical mechanism of basal Numb localization (multivalent PTB-Pon phase separation), and uncovered NUMB-EFA6B-ARF6 control of Rac1 recycling and a role in mitochondrial fission via Drp1/ROCK.","evidence":"Structural analysis and in vitro phase separation with mutagenesis and Drosophila imaging; in vitro GEF assay, Co-IP, migration assays; conditional KO with phospho-Drp1 and pharmacological rescue","pmids":["29467404","30061108","29890853"],"confidence":"High","gaps":["Whether phase separation occurs in mammalian cortical asymmetry untested","Drp1/ROCK finding medium-confidence single-lab"]},{"year":2020,"claim":"Reported a context-dependent reversal in which NUMB stabilizes N1ICD by recruiting BAP1, independent of its endocytic role, challenging the canonical Notch-inhibitory model.","evidence":"Co-IP, ubiquitination assay, BAP1 catalytic mutant, N1ICD stability in cortical neural progenitors","pmids":["31504682"],"confidence":"Medium","gaps":["Contradicts established Notch-inhibitory role; reconciliation not established","Single lab"]},{"year":2022,"claim":"Connected Numb to neuronal proteostasis and to mitophagy-linked metabolic reprogramming, identifying Tau-level regulation and a Numb/Parkin axis controlling lineage plasticity.","evidence":"Conditional Numb KO and isoform overexpression in neurons with TauP301S cross; Numb-Parkin Co-IP, mitophagy and metabolomic/lactylation assays in tumor lines","pmids":["36260685","36724072"],"confidence":"High","gaps":["Mechanism by which Numb lowers Tau not defined","Numb-Parkin finding medium-confidence single-lab"]},{"year":2023,"claim":"Defined a density-sensing role in which phospho-SPTAN1 recruits long NUMB isoforms to membrane to sequester MARK kinases, activating Hippo/MST1-2 to suppress YAP for contact inhibition.","evidence":"Co-IP, isoform-specific and liver-specific KO, phospho-SPTAN1 and Hippo kinase activity assays","pmids":["37843276"],"confidence":"High","gaps":["Structural basis of MARK sequestration not resolved"]},{"year":2024,"claim":"Localized Numb to the ciliary pocket as a clathrin adaptor exporting Ptch1 from the cilium, defining a positive role in Hedgehog signaling and neural progenitor differentiation.","evidence":"Proximity proteomics, live imaging of Ptch1 ciliary exit, cerebellar conditional KO, differentiation assays","pmids":["38664376"],"confidence":"High","gaps":["How Numb selectively targets ciliary-pocket cargo unresolved"]},{"year":null,"claim":"It remains unresolved how a single adaptor selects between opposing post-endocytic fates (degradation versus recycling) for different cargoes and how its endocytic, p53-protective, and Hippo-regulatory activities are integrated within one cell.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking cargo identity to sorting outcome","Structural basis of the p53-MDM2 tricomplex not solved","Conditions favoring Notch inhibition vs N1ICD stabilization not reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,7,9,23]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[1,7,15,23,27]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,8,12,24]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,2,6,23]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,10,11,25]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[6,9,15]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[23]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,2,7,9,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,23,24,27]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2,15,23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,4,8,12,19]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,28,19]}],"complexes":[],"partners":["NOTCH1","ITCH","MDM2","TP53","AP2A (ALPHA-ADAPTIN)","RAB7","VEGFR2","SPTAN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49757","full_name":"Protein numb homolog","aliases":["Protein S171"],"length_aa":651,"mass_kda":70.8,"function":"Regulates clathrin-mediated receptor endocytosis (PubMed:18657069). Plays a role in the process of neurogenesis (By similarity). Required throughout embryonic neurogenesis to maintain neural progenitor cells, also called radial glial cells (RGCs), by allowing their daughter cells to choose progenitor over neuronal cell fate (By similarity). Not required for the proliferation of neural progenitor cells before the onset of neurogenesis. Also involved postnatally in the subventricular zone (SVZ) neurogenesis by regulating SVZ neuroblasts survival and ependymal wall integrity (By similarity). May also mediate local repair of brain ventricular wall damage (By similarity)","subcellular_location":"Cell membrane; Endosome membrane","url":"https://www.uniprot.org/uniprotkb/P49757/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NUMB","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"AP2B1","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NUMB","total_profiled":1310},"omim":[{"mim_id":"612771","title":"DUAL OXIDASE MATURATION FACTOR 1; DUOXA1","url":"https://www.omim.org/entry/612771"},{"mim_id":"609733","title":"LIGAND OF NUMB PROTEIN X2; LNX2","url":"https://www.omim.org/entry/609733"},{"mim_id":"609732","title":"LIGAND OF NUMB PROTEIN X1; LNX1","url":"https://www.omim.org/entry/609732"},{"mim_id":"608232","title":"LEUKEMIA, CHRONIC MYELOID; CML","url":"https://www.omim.org/entry/608232"},{"mim_id":"607897","title":"MUSASHI RNA BINDING PROTEIN 2; MSI2","url":"https://www.omim.org/entry/607897"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cell Junctions","reliability":"Uncertain"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NUMB"},"hgnc":{"alias_symbol":[],"prev_symbol":["C14orf41"]},"alphafold":{"accession":"P49757","domains":[{"cath_id":"2.30.29.30","chopping":"17-174","consensus_level":"high","plddt":90.8807,"start":17,"end":174},{"cath_id":"-","chopping":"176-217","consensus_level":"medium","plddt":74.53,"start":176,"end":217}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49757","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49757-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49757-F1-predicted_aligned_error_v6.png","plddt_mean":59.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUMB","jax_strain_url":"https://www.jax.org/strain/search?query=NUMB"},"sequence":{"accession":"P49757","fasta_url":"https://rest.uniprot.org/uniprotkb/P49757.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49757/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49757"}},"corpus_meta":[{"pmid":"7566172","id":"PMC_7566172","title":"Asymmetric 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E-cadherin endocytosis through p120 catenin with aPKC.","date":"2011","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/21775625","citation_count":93,"is_preprint":false},{"pmid":"25134838","id":"PMC_25134838","title":"NUMB inhibition of NOTCH signalling as a therapeutic target in prostate cancer.","date":"2014","source":"Nature reviews. 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cell-like properties and resistance to chemotherapy.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27613838","citation_count":37,"is_preprint":false},{"pmid":"15798180","id":"PMC_15798180","title":"Numb proteins specify asymmetric cell fates via an endocytosis- and proteasome-independent pathway.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15798180","citation_count":36,"is_preprint":false},{"pmid":"16832352","id":"PMC_16832352","title":"Ligand-of-Numb protein X is an endocytic scaffold for junctional adhesion molecule 4.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16832352","citation_count":36,"is_preprint":false},{"pmid":"14670962","id":"PMC_14670962","title":"A novel transmembrane protein recruits numb to the plasma membrane during asymmetric cell division.","date":"2003","source":"The Journal of biological 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metaplasia.","date":"2013","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/23891977","citation_count":30,"is_preprint":false},{"pmid":"27009199","id":"PMC_27009199","title":"RBM4 promotes neuronal differentiation and neurite outgrowth by modulating Numb isoform expression.","date":"2016","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/27009199","citation_count":30,"is_preprint":false},{"pmid":"35738348","id":"PMC_35738348","title":"Numb-associated kinases are required for SARS-CoV-2 infection and are cellular targets for antiviral strategies.","date":"2022","source":"Antiviral research","url":"https://pubmed.ncbi.nlm.nih.gov/35738348","citation_count":30,"is_preprint":false},{"pmid":"31894898","id":"PMC_31894898","title":"miR-335 modulates Numb alternative splicing via targeting RBM10 in endometrial cancer.","date":"2020","source":"The Kaohsiung journal of medical 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regulates Hedgehog signaling at the ciliary pocket.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38664376","citation_count":22,"is_preprint":false},{"pmid":"34078527","id":"PMC_34078527","title":"The role of NUMB/NUMB isoforms in cancer stem cells.","date":"2021","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/34078527","citation_count":22,"is_preprint":false},{"pmid":"28060745","id":"PMC_28060745","title":"Expression of Notch1 and Numb in small cell lung cancer.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28060745","citation_count":22,"is_preprint":false},{"pmid":"34667161","id":"PMC_34667161","title":"Loss of Numb promotes hepatic progenitor expansion and intrahepatic cholangiocarcinoma by enhancing Notch signaling.","date":"2021","source":"Cell death & 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recycling route controls apically restricted cell protrusions and mesenchymal motility.","date":"2018","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30061108","citation_count":18,"is_preprint":false},{"pmid":"31114254","id":"PMC_31114254","title":"Numb inhibits cell proliferation, invasion, and epithelial-mesenchymal transition through PAK1/β-catenin signaling pathway in ovarian cancer.","date":"2019","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31114254","citation_count":18,"is_preprint":false},{"pmid":"32888910","id":"PMC_32888910","title":"Numb ameliorates necrosis and inflammation in acute kidney injury induced by cisplatin.","date":"2020","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/32888910","citation_count":18,"is_preprint":false},{"pmid":"26069237","id":"PMC_26069237","title":"Regulation of vascular endothelial growth factor receptor function in angiogenesis by numb and numb-like.","date":"2015","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26069237","citation_count":18,"is_preprint":false},{"pmid":"23624653","id":"PMC_23624653","title":"Overexpression of Numb suppresses tumor cell growth and enhances sensitivity to cisplatin in epithelioid malignant pleural mesothelioma.","date":"2013","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23624653","citation_count":18,"is_preprint":false},{"pmid":"37843276","id":"PMC_37843276","title":"SPTAN1/NUMB axis senses cell density to restrain cell growth and oncogenesis through Hippo signaling.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37843276","citation_count":17,"is_preprint":false},{"pmid":"21939656","id":"PMC_21939656","title":"NUMB does not impair growth and differentiation status of experimental gliomas.","date":"2011","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/21939656","citation_count":17,"is_preprint":false},{"pmid":"34990618","id":"PMC_34990618","title":"Numb inhibits migration and promotes proliferation of colon cancer cells via RhoA/ROCK signaling pathway repression.","date":"2022","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34990618","citation_count":16,"is_preprint":false},{"pmid":"29356167","id":"PMC_29356167","title":"Targeting of miR-31/96/182 to the Numb gene during head and neck oncogenesis.","date":"2018","source":"Head & neck","url":"https://pubmed.ncbi.nlm.nih.gov/29356167","citation_count":16,"is_preprint":false},{"pmid":"21179188","id":"PMC_21179188","title":"Zebrafish numb and numblike are involved in primitive erythrocyte differentiation.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21179188","citation_count":16,"is_preprint":false},{"pmid":"36672267","id":"PMC_36672267","title":"The Multitasker Protein: A Look at the Multiple Capabilities of NUMB.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36672267","citation_count":15,"is_preprint":false},{"pmid":"32088828","id":"PMC_32088828","title":"CD82-TRPM7-Numb signaling mediates age-related cognitive impairment.","date":"2020","source":"GeroScience","url":"https://pubmed.ncbi.nlm.nih.gov/32088828","citation_count":15,"is_preprint":false},{"pmid":"35345586","id":"PMC_35345586","title":"ATP11A promotes EMT by regulating Numb PRRL in pancreatic cancer cells.","date":"2022","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/35345586","citation_count":15,"is_preprint":false},{"pmid":"36260685","id":"PMC_36260685","title":"Numb regulates Tau levels and prevents neurodegeneration in tauopathy mouse models.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36260685","citation_count":14,"is_preprint":false},{"pmid":"29339436","id":"PMC_29339436","title":"Rewired Notch/p53 by Numb'ing Mdm2.","date":"2018","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29339436","citation_count":14,"is_preprint":false},{"pmid":"25788995","id":"PMC_25788995","title":"Role of Numb expression and nuclear translocation in endometrial cancer.","date":"2015","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/25788995","citation_count":14,"is_preprint":false},{"pmid":"33474726","id":"PMC_33474726","title":"Complex wall materials of polysaccharide and protein effectively protected numb-taste substance degradation of Zanthoxylum bungeanum.","date":"2021","source":"Journal of the science of food and agriculture","url":"https://pubmed.ncbi.nlm.nih.gov/33474726","citation_count":14,"is_preprint":false},{"pmid":"36941658","id":"PMC_36941658","title":"BM-MSCs overexpressing the Numb enhance the therapeutic effect on cholestatic liver fibrosis by inhibiting the ductular reaction.","date":"2023","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/36941658","citation_count":14,"is_preprint":false},{"pmid":"35599603","id":"PMC_35599603","title":"SLC8A1 antisense RNA 1 suppresses papillary thyroid cancer malignant progression via the FUS RNA binding protein (FUS)/NUMB like endocytic adaptor protein (Numbl) axis.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35599603","citation_count":14,"is_preprint":false},{"pmid":"16701985","id":"PMC_16701985","title":"Zebrafish Numb homologue: phylogenetic evolution and involvement in regulation of left-right asymmetry.","date":"2006","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/16701985","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45092,"output_tokens":8817,"usd":0.133766,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18534,"output_tokens":7105,"usd":0.135148,"stage2_stop_reason":"end_turn"},"total_usd":0.268914,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Numb protein localizes asymmetrically during cell division and segregates into one daughter cell, where it is required for specification of correct cell fate. Its localization is coupled to mitosis, correlated with centrosome position, and is independent of microtubules and actin.\",\n      \"method\": \"Genetic loss-of-function, cytochalasin D treatment, nocodazole treatment, immunolocalization in Drosophila neuroblasts\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments with functional consequence, replicated across multiple labs subsequently\",\n      \"pmids\": [\"7566172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Numb is an endocytic protein that localizes to endocytic organelles, is co-trafficked with internalizing receptors, and associates with the appendage domain of alpha-adaptin (a subunit of AP2/clathrin-coated pits). Dominant-negative Numb fragments inhibit both constitutive and ligand-regulated receptor-mediated internalization.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation with alpha-adaptin, dominant-negative overexpression, receptor internalization assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, dominant-negative functional assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11121447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In Drosophila sensory organ precursor cells, Numb acts by polarizing the distribution of alpha-Adaptin (required for receptor-mediated endocytosis). Alpha-Adaptin binds to Numb and localizes asymmetrically in a Numb-dependent fashion. Mutant alpha-Adaptin unable to bind Numb fails to localize asymmetrically and causes numb-like fate defects. Numb also binds the intracellular domain of Notch.\",\n      \"method\": \"Co-immunoprecipitation, genetic loss-of-function, binding-deficient mutant analysis, asymmetric division assay in Drosophila SOPs\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus mutagenesis plus genetic epistasis, replicated in multiple contexts\",\n      \"pmids\": [\"12194853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mammalian Numb promotes ubiquitination of membrane-bound Notch1 receptor via its PTB domain, resulting in degradation of the Notch1 intracellular domain and loss of Notch-dependent transcriptional activation. Numb interacts with the HECT domain E3 ligase Itch, and Numb and Itch act cooperatively to ubiquitinate membrane-tethered Notch1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Hes1-luciferase reporter assay, PTB domain mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro ubiquitination assay, Co-IP, reporter assay with domain mutant, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12682059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human Numb is a substrate of MDM2 ubiquitin ligase; recombinant hNumb binds MDM2 in vitro and is ubiquitinated by MDM2 in an E1/E2/MDM2-dependent manner requiring the RING-finger domain. Co-transfection of hNumb and MDM2 in U2OS cells leads to Numb ubiquitination and degradation.\",\n      \"method\": \"In vitro ubiquitination assay with recombinant proteins, co-immunoprecipitation, co-transfection with RING-finger mutant MDM2\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted ubiquitination assay plus active-site mutagenesis plus cell-based confirmation, single lab\",\n      \"pmids\": [\"12646252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CRMP-2 interacts with Numb, and the CRMP-2/Numb complex localizes to axonal growth cones where Numb associates with L1 (a neuronal adhesion molecule undergoing endocytosis). Dominant-negative CRMP-2 or CRMP-2 siRNA inhibits endocytosis of L1 at growth cones and suppresses axon growth.\",\n      \"method\": \"Co-immunoprecipitation, colocalization by immunofluorescence, dominant-negative overexpression, siRNA knockdown, L1 endocytosis assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, siRNA and dominant-negative with defined functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"12942088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In Drosophila SOP cells, Numb induces endocytosis of Sanpodo (a four-pass transmembrane protein that enables Notch signaling) via alpha-Adaptin-dependent clathrin-mediated endocytosis. Numb binds Sanpodo through its PTB domain. In numb or alpha-adaptin mutants, Sanpodo is not endocytosed. Numb regulates this endocytosis throughout the cell cycle, not only after division.\",\n      \"method\": \"Genetic loss-of-function (numb, alpha-adaptin mutants), co-localization with Rab5/Rab7 endosomal markers, PTB domain binding assay, Drosophila SOP imaging\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis plus binding domain analysis plus endosomal colocalization, replicated across multiple genetic backgrounds\",\n      \"pmids\": [\"16113648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Numb is an endocytic adaptor required for directional integrin endocytosis during cell migration. Numb binds integrin-beta subunits and localizes to clathrin-coated structures at the leading edge. RNAi knockdown of Numb impairs integrin endocytosis and directional cell migration. aPKC phosphorylates Numb, releasing it from clathrin-coated structures and preventing integrin binding. Numb interacts with the aPKC-binding partner PAR-3.\",\n      \"method\": \"RNAi knockdown, co-immunoprecipitation, live-cell and fixed immunofluorescence, integrin endocytosis assay, phosphorylation assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with defined cellular phenotype, Co-IP, phosphorylation assay, multiple orthogonal methods\",\n      \"pmids\": [\"17609107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NUMB enters a tricomplex with p53 and the E3 ubiquitin ligase HDM2/MDM2, thereby preventing ubiquitination and degradation of p53. This results in increased p53 protein levels and activity, and regulation of p53-dependent phenotypes. The PTB domain of NUMB is required for this function.\",\n      \"method\": \"Co-immunoprecipitation (tricomplex), ubiquitination assay, p53 stability/activity assays, domain mapping, breast cancer cell lines\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP of tricomplex, ubiquitination assay, multiple cancer cell lines, replicated in primary tumor cells\",\n      \"pmids\": [\"18172499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mammalian Notch1 is constitutively internalized and trafficked to recycling and late endosomal compartments. Numb overexpression promotes sorting of Notch1 to late endosomes for degradation; Numb depletion facilitates Notch1 recycling. Numb mutants lacking Itch interaction or endocytic protein-binding motifs fail to promote Notch1 degradation.\",\n      \"method\": \"Fluorescence microscopy of endosomal trafficking, Numb knockdown/overexpression, Numb mutant analysis, co-immunoprecipitation with Itch\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live trafficking assay, loss-of-function, domain mutants with defined trafficking readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19567869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Numb interacts with E-cadherin through its PTB domain and regulates E-cadherin localization at lateral cell-cell junctions. Numb also binds Par3 in polarized MDCK cells. After Src activation or HGF treatment, Numb dissociates from E-cadherin/Par3 and associates preferentially with aPKC-Par6, sequestering aPKC in the cytosol. Numb knockdown causes basolateral-to-apicolateral E-cadherin translocation, elevated actin polymerization, decreased cell-cell adhesion, and increased migration.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, confocal microscopy, cell scattering assay, E-cadherin localization\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, shRNA with defined polarity/adhesion phenotype, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"19609305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Numb directly interacts with p120 catenin (which is bound to E-cadherin and prevents its internalization). Numb accumulates at intercellular adhesion sites; its depletion impairs E-cadherin internalization while p120 depletion accelerates it. aPKC phosphorylates Numb and inhibits its association with p120 and alpha-adaptin, thereby attenuating E-cadherin endocytosis. A phosphomimetic Numb mutant or an alpha-adaptin-binding-deficient mutant fails to restore E-cadherin internalization.\",\n      \"method\": \"Co-immunoprecipitation, RNAi depletion, phosphomimetic/binding-deficient mutant analysis, E-cadherin internalization assay, aPKC kinase assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay plus Co-IP plus mutagenesis plus internalization assay with multiple controls, single lab\",\n      \"pmids\": [\"21775625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MDM2 uses a dual-site mechanism (N-terminal hydrophobic pocket and acidic domain) to bind and ubiquitinate NUMB, analogous to its interaction with p53. Only one region within the PTB domain of NUMB (amino acids 113–148) mediates binding to both MDM2 domains. By binding to both MDM2 domains, NUMB disrupts the MDM2-p53 complex and inhibits MDM2-catalyzed ubiquitination of p53.\",\n      \"method\": \"In vitro binding assays, ubiquitination assay, domain deletion and point-mutant analysis, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted ubiquitination assay plus domain mutagenesis, mechanistically detailed, single lab\",\n      \"pmids\": [\"22337874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Numb knockdown causes G2/M arrest and reduced cell growth in melanoma cells. Numb co-immunoprecipitates with and colocalizes with polo-like kinase Plk1; Numb cycles in a cell-cycle-dependent manner with Plk1. Numb expression is required for Plk1 protein stability and proper localization to spindle poles during mitosis. Numb reduction leads to mislocalized Plk1 and disorganized gamma-tubulin at centrosomes.\",\n      \"method\": \"Co-immunoprecipitation, colocalization, siRNA knockdown, cell cycle analysis, immunofluorescence of spindle poles\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and colocalization with defined cellular phenotype, single lab, single set of methods\",\n      \"pmids\": [\"22593191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"All four Numb isoforms negatively regulate Notch1 in transcription and myogenic differentiation assays. Notch3 is not polyubiquitinated nor degraded when co-expressed with Numb. Unlike Notch1, Notch3 is not a target of Numb-mediated ubiquitination, demonstrating receptor-specific regulation.\",\n      \"method\": \"Transcription reporter assay, myogenic differentiation assay, ubiquitination assay with co-expressed proteins\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional assay plus ubiquitination assay, single lab, limited replication\",\n      \"pmids\": [\"21356309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In cardiac development, NUMB and NUMBL are required for downregulation of ERBB2 signaling by promoting ERBB2 transition from early to late endosomes for degradation via interaction with the small GTPase Rab7. Loss of NUMB/NUMBL causes a partial block of late endosome formation, sustained ERBB2/STAT5 signaling, YAP1 nuclear localization, and aberrant cardiomyocyte proliferation resulting in ventricular noncompaction.\",\n      \"method\": \"Cardiac-specific double knockout, endosomal fractionation, co-immunoprecipitation with Rab7, rescue by heterozygous ERBB2 or YAP1 loss-of-function\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular phenotype, Co-IP with Rab7, genetic rescue experiments, multiple orthogonal methods\",\n      \"pmids\": [\"28067668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Numb PTB domain, using two distinct binding surfaces, recognizes repeating motifs within Pon in a multivalent manner. This multivalent Numb-Pon interaction leads to liquid-liquid phase separation of the complex, forming basal condensates in Drosophila neuroblasts. Perturbation of this phase transition impairs basal localization of Numb and subsequent suppression of Notch signaling during asymmetric neuroblast division.\",\n      \"method\": \"Crystal structure/structural analysis of PTB-Pon interaction, in vitro phase separation assay, mutagenesis of binding surfaces, Drosophila live imaging of Numb localization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural analysis plus in vitro reconstitution of phase separation plus mutagenesis plus in vivo functional validation, single lab\",\n      \"pmids\": [\"29467404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Numb depletion from proximal tubules promotes mitochondrial fragmentation by increasing phosphorylation of Drp1 at Ser637 (mouse Ser656), which recruits Drp1 to mitochondria. ROCK kinase inhibition (Y-27632) attenuates Drp1 phosphorylation and fragmentation in Numb-deficient cells. Drp1 inhibitor mdivi-1 restores mitochondrial morphology in Numb-KO mice.\",\n      \"method\": \"Proximal tubule-specific Numb KO mice, phospho-Drp1 western blot, ROCK inhibitor treatment, Drp1 inhibitor rescue, electron microscopy\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined mitochondrial phenotype plus pharmacological rescue, single lab\",\n      \"pmids\": [\"29890853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NUMB and NUMBL interact with VEGFR2 and VEGFR3, controlling VEGF receptor endocytosis, signaling activation, and recycling back to the plasma membrane. Inducible endothelial-specific inactivation of Numb/Numbl impairs vessel growth, reduces endothelial proliferation/sprouting, and decreases VEGF receptor activation.\",\n      \"method\": \"Co-immunoprecipitation with VEGFR2/3, inducible endothelial-specific KO mice, receptor recycling assay, retinal angiogenesis imaging\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus conditional KO with defined angiogenic phenotype, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"26069237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Plk1 phosphorylates Numb, leading to enhanced proteasomal degradation of Numb and impaired Numb/p53 pathway. Cells carrying the unphosphorylated form of Numb are more sensitive to doxorubicin. This identifies a mechanism by which Plk1 antagonizes p53 during DNA damage response via Numb destabilization.\",\n      \"method\": \"In vitro Plk1 kinase assay, proteasome inhibitor experiments, phosphomimetic/unphosphorylatable Numb mutants, doxorubicin sensitivity assay, xenograft mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay plus mutagenesis plus cell-based and in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29059161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NUMB binds directly to the ARF6 guanine nucleotide exchange factor EFA6B through its PTB domain (recognizing an N-terminal NPLF motif) and promotes EFA6B exchange activity in vitro. A NUMB-EFA6B-ARF6 axis regulates recycling of RAC1 and is critical for formation of circular dorsal ruffles and acquisition of mesenchymal migration. Loss of NUMB promotes HGF-induced cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation, in vitro GEF activity assay, PTB domain mutant analysis, RNAi knockdown, cell migration/invasion assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro GEF assay plus Co-IP plus domain mutagenesis plus functional migration assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30061108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NUMB stabilizes the NOTCH1 intracellular domain (N1ICD) by recruiting the deubiquitinase BAP1 to N1ICD, facilitating the BAP1-BRCA1 complex interaction with N1ICD to reduce its ubiquitination. This stabilization is independent of NUMB's role in endocytosis. BAP1 stabilizes N1ICD independent of its DUB catalytic activity but relying on its BRCA1-inhibiting function.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, BAP1 catalytic mutant analysis, N1ICD stability assay, cortical neural progenitor cell assay\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ubiquitination assay with mutant analysis, single lab, contradicts canonical Notch-inhibitory role of NUMB\",\n      \"pmids\": [\"31504682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Numb binds Parkin and facilitates Parkin-mediated mitophagy (mitochondrial quality control). Deficiency in the Numb/Parkin pathway in prostate or lung adenocarcinomas causes metabolic reprogramming with increased lactate production, upregulation of histone lactylation, and transcription of neuroendocrine-associated genes driving cell fate transition.\",\n      \"method\": \"Co-immunoprecipitation (Numb-Parkin binding), mitophagy assay, Numb KO cell lines, metabolomics, histone lactylation measurement\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP for Numb-Parkin interaction plus KO phenotype with metabolic readouts, single lab\",\n      \"pmids\": [\"36724072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Numb localizes to the ciliary pocket and acts as an endocytic adaptor to incorporate Ptch1 into clathrin-coated vesicles, promoting Ptch1 exit from the cilium. Loss of Numb impedes Shh-induced Ptch1 exit from the cilium, reduces Hedgehog signaling, impairs Shh-induced neural progenitor differentiation, and reduces cerebellar granule cell precursor proliferation in vivo.\",\n      \"method\": \"Proximity labeling and quantitative proteomics (ciliary Numb identification), live imaging of Ptch1 ciliary exit, Numb conditional KO in cerebellum, neural progenitor differentiation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity proteomics plus live imaging plus conditional KO with multiple cellular phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"38664376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"High cell density induces phosphorylation of SPTAN1 (spectrin alpha), which recruits NUMB isoforms 1 and 2 (long PTB-containing isoforms) to the plasma membrane. NUMB then sequesters MARK kinases at the membrane, rendering them inaccessible for phosphorylation and inhibition of Hippo kinases MST1/2, thereby activating Hippo signaling and blocking YAP activity for cell contact inhibition. Low cell density leads to SPTAN1 dephosphorylation and NUMB cytoplasmic relocation, releasing MARKs to inhibit MST1/2 and activate YAP.\",\n      \"method\": \"Co-immunoprecipitation (NUMB-SPTAN1, NUMB-MARK), NUMB isoform-specific KO, liver-specific double KO (NUMB/WW45), phospho-SPTAN1 assays, Hippo kinase activity assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KO phenotype with tumorigenesis readout, kinase activity assay, isoform specificity established, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37843276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A novel transmembrane protein NIP (Numb-interacting protein) contains NXXF motifs that bind the PTB domain of Numb. Expression of NIP in COS-7 cells recruits Numb from cytosol to plasma membrane in a NXXF-dependent manner. RNAi knockdown of NIP in Drosophila S2 cells releases Numb to the cytosol. In dividing Drosophila neuroblasts, NIP colocalizes with Numb in a basal cortical crescent.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, membrane recruitment assay, immunofluorescence in Drosophila neuroblasts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP, RNAi, and localization data, single lab, mechanistically informative for plasma membrane targeting\",\n      \"pmids\": [\"14670962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LNX1 (Ligand-of-Numb protein X1) provides an endocytic scaffold for JAM4; LNX1 facilitates endocytosis of JAM4, and Numb is necessary for LNX1-mediated JAM4 endocytosis. JAM4, LNX1, and Numb form a tripartite complex in vitro. LNX1 is involved in TGF-beta-induced redistribution of JAM4.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation from kidney lysates, in vitro tripartite complex reconstitution, dominant-negative and RNAi experiments, endocytosis assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro complex reconstitution plus RNAi plus Co-IP from tissue, single lab\",\n      \"pmids\": [\"16832352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Numb directly interacts with VEGFR2 and VEGFR3 and controls their endocytosis and recycling. Numb proteins counteract VEGF receptor degradation and promote VEGFR2 recycling to the plasma membrane, sustaining VEGF receptor activation in response to ligand.\",\n      \"method\": \"Co-immunoprecipitation, receptor recycling/degradation assay, Numb/Numbl inducible endothelial KO, VEGF signaling assays\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, receptor trafficking assay, conditional KO with angiogenic phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"26069237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Genetic epistasis in Drosophila CNS shows that both Notch and Numb function downstream of cell division genes (cyclinA, rca1, string/cdc25). In the absence of cell cycle entry into metaphase, Numb protein prevents Notch signaling from specifying sib fate; progression through the cell cycle is required for asymmetric localization of Numb.\",\n      \"method\": \"Genetic epistasis using loss-of-function mutations in cyclinA, rca1, stg, numb, Notch; double-mutant analysis; nocodazole treatment\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-gene epistasis with double and triple mutants, well-controlled genetic study\",\n      \"pmids\": [\"10331986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Numb regulates intracellular Tau levels; conditional inactivation of Numb in retinal ganglion cells increases Tau levels and leads to axonal blebbing and neuronal loss. In the TauP301S tauopathy model, conditional Numb inactivation accelerates neurodegeneration. Overexpression of the long Numb isoform (Numb-72) decreases intracellular Tau levels and reduces axonal blebbing.\",\n      \"method\": \"Conditional KO of Numb in RGCs and spinal motoneurons, TauP301S cross, Tau level quantification by western blot, axonal blebbing assay, behavioral test, electrophysiology of cultured neurons\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO plus gain-of-function with multiple cellular and in vivo phenotypes, single lab with orthogonal methods\",\n      \"pmids\": [\"36260685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The splicing factors ASF/SF2 and PTBP1 regulate alternative splicing of Numb exon 9 (E9). Activation of the MAPK/ERK pathway promotes E9 inclusion (producing p72/p71 isoforms) in cancer cells, switching Numb isoform expression from E9-excluded (differentiated cell) to E9-included (progenitor) forms.\",\n      \"method\": \"Splicing reporter assay, siRNA knockdown of splicing factors, MEK/ERK inhibitor and activator treatment, RT-PCR isoform analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — splicing reporter assay plus RNAi plus pharmacological pathway manipulation, single lab\",\n      \"pmids\": [\"27041567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Numb is required for preventing p53-dependent senescence in skeletal muscle stem cells following injury. In Numb-deficient satellite cells, senescence is rescued to wild-type levels by antioxidant treatment or p53 ablation, establishing that Numb acts upstream of p53 to prevent oxidative stress-induced senescence.\",\n      \"method\": \"Conditional Numb KO in muscle satellite cells, antioxidant treatment rescue, p53 genetic ablation rescue, senescence assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined senescence phenotype plus genetic rescue (p53 ablation) plus pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"26503169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Numb depletion in MDCK cells destabilizes E-cadherin-based cell-cell adhesion and promotes loss of epithelial cell morphology. Numb knockdown potentiates HGF-induced lamellipodia formation and cell dispersal via hyperactivation of Rac1-GTP. Rac1 inhibition in Numb-depleted cells stabilizes cell-cell contacts, establishing that Numb acts to suppress Rac1-GTP accumulation.\",\n      \"method\": \"shRNA knockdown, Rac1-GTP pull-down assay, Rac1 inhibitor rescue, HGF-stimulated cell scattering assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RNAi with defined cellular phenotype and Rac1-GTP biochemical readout, single lab\",\n      \"pmids\": [\"21147098\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUMB is a multi-functional endocytic adaptor protein that asymmetrically segregates at cell division to act as a cell fate determinant; it inhibits Notch signaling by recruiting the E3 ligase Itch to ubiquitinate membrane Notch1 and by directing post-endocytic sorting of Notch1 to late endosomes for degradation, while simultaneously protecting p53 from MDM2-mediated ubiquitination by forming a tricomplex with p53 and MDM2; it controls directional trafficking of integrins, E-cadherin, VEGF receptors, and Ptch1 via clathrin/AP2-dependent endocytosis, regulated by aPKC phosphorylation; it undergoes liquid-liquid phase separation with its basal cortical partner Pon; it suppresses Rac1 and RhoA/ROCK-mediated migration; it facilitates Parkin-mediated mitophagy; and it senses cell density by binding phospho-SPTAN1 to activate Hippo/MST1/2 signaling and suppress YAP.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NUMB is a multifunctional endocytic adaptor and cell-fate determinant that segregates asymmetrically during mitosis to specify daughter-cell identity, a process coupled to cell-cycle progression and centrosome position but independent of microtubules and actin [#0, #28]. Its membrane-proximal localization in dividing cells is achieved through multivalent PTB-domain engagement of cortical partners: in Drosophila neuroblasts NUMB recognizes repeating motifs in Pon to drive liquid-liquid phase separation into basal condensates required for Notch suppression [#16], and is recruited to the cortex by the transmembrane protein NIP [#25]. Mechanistically NUMB functions as an endocytic adaptor that binds the alpha-adaptin appendage of the AP2/clathrin machinery to drive receptor-mediated internalization and post-endocytic sorting [#1, #2]. Through its PTB domain it engages numerous transmembrane cargoes and routes them to defined endosomal fates—it promotes Itch-dependent ubiquitination and late-endosomal degradation of Notch1 [#3, #9], directs Sanpodo endocytosis [#6], and channels ERBB2 from early to late endosomes via Rab7 for degradation [#15], while conversely sustaining VEGFR2/3 by promoting their recycling to the plasma membrane [#27]. This adaptor activity is switched off by aPKC phosphorylation, which releases NUMB from clathrin structures and abolishes integrin and E-cadherin/p120-catenin binding, coupling NUMB-dependent trafficking to cell polarity and directional migration [#7, #11]. NUMB additionally stabilizes p53 by entering a tricomplex with p53 and the E3 ligase MDM2, occupying both MDM2 substrate-binding surfaces to block p53 ubiquitination—itself being an MDM2 substrate—thereby restraining oxidative-stress-induced senescence [#4, #8, #12, #31]. Plk1 phosphorylates NUMB to trigger its proteasomal degradation, antagonizing the NUMB-p53 axis during DNA damage [#19]. Beyond these core roles NUMB suppresses Rac1/RhoA-driven migration [#20, #32], facilitates Parkin-mediated mitophagy [#22], removes Ptch1 from the ciliary pocket to support Hedgehog signaling [#23], and senses cell density via phospho-SPTAN1 to sequester MARK kinases and activate Hippo/MST1-2 signaling to restrain YAP [#24].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that Numb is a cell-fate determinant by showing it asymmetrically segregates into one daughter cell at division, linking a molecular asymmetry to a developmental decision.\",\n      \"evidence\": \"Genetic loss-of-function and immunolocalization in Drosophila neuroblasts with cytoskeletal drug treatments\",\n      \"pmids\": [\"7566172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism establishing the asymmetric cortical crescent not defined\", \"Downstream effector of fate specification not identified at this stage\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Placed Numb and Notch genetically downstream of cell-cycle genes, showing that mitotic progression is required for Numb asymmetric localization and Notch inhibition.\",\n      \"evidence\": \"Multi-gene genetic epistasis (cyclinA, rca1, stg, numb, Notch) in Drosophila CNS\",\n      \"pmids\": [\"10331986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical coupling between cell-cycle machinery and Numb localization not resolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified Numb as an endocytic adaptor by demonstrating it binds the alpha-adaptin AP2 appendage and is required for receptor internalization, providing a molecular activity underlying fate determination.\",\n      \"evidence\": \"Subcellular fractionation, alpha-adaptin Co-IP, and dominant-negative receptor internalization assays\",\n      \"pmids\": [\"11121447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific cargoes endocytosed in vivo not yet defined\", \"Connection of endocytosis to Notch inhibition not yet established\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected Numb's endocytic and fate-determining roles by showing Numb polarizes alpha-Adaptin distribution and binds the Notch intracellular domain, with alpha-Adaptin binding required for asymmetric localization.\",\n      \"evidence\": \"Co-IP, binding-deficient mutant analysis, and genetic epistasis in Drosophila SOPs\",\n      \"pmids\": [\"12194853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which endocytosis suppresses Notch signaling not yet biochemically defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined a biochemical mechanism of Notch inhibition: Numb recruits the HECT E3 ligase Itch via its PTB domain to ubiquitinate and degrade membrane Notch1, abolishing Notch transcriptional output.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination assay, Hes1-luciferase reporter, PTB-mutant analysis in mammalian cells\",\n      \"pmids\": [\"12682059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endosomal compartment of degradation not yet defined\", \"Receptor specificity beyond Notch1 untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed reciprocal regulation by identifying Numb as an MDM2 substrate, and uncovered new endocytic cargoes (L1 via CRMP-2; NIP-mediated membrane recruitment), broadening Numb's adaptor repertoire.\",\n      \"evidence\": \"In vitro reconstituted ubiquitination with RING mutants; CRMP-2/L1 Co-IP and endocytosis assays; NIP membrane-recruitment and RNAi assays\",\n      \"pmids\": [\"12646252\", \"12942088\", \"14670962\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of MDM2-mediated Numb turnover unclear at this stage\", \"NIP interaction confidence medium (single lab)\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that Numb regulates cargo endocytosis (Sanpodo) throughout the cell cycle via alpha-Adaptin-dependent clathrin endocytosis, extending its adaptor role beyond post-division fate specification.\",\n      \"evidence\": \"Genetic loss-of-function, Rab5/Rab7 colocalization, PTB-binding assays in Drosophila SOPs\",\n      \"pmids\": [\"16113648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link from Sanpodo endocytosis to Notch activation state incompletely mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended Numb adaptor function to LNX1-scaffolded JAM4 endocytosis, defining a tripartite complex and a role in junctional protein trafficking.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP from kidney lysates, in vitro tripartite reconstitution, RNAi endocytosis assay\",\n      \"pmids\": [\"16832352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context of JAM4 regulation by Numb single-lab only\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated that aPKC phosphorylation acts as a molecular switch releasing Numb from clathrin structures, coupling Numb-dependent integrin endocytosis to polarized directional migration.\",\n      \"evidence\": \"RNAi, Co-IP, phosphorylation assay, integrin endocytosis and migration assays\",\n      \"pmids\": [\"17609107\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"aPKC phosphosites on Numb not mapped here\", \"Generality of the switch to other cargoes not yet tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established a tumor-suppressive role by showing NUMB forms a tricomplex with p53 and MDM2 to protect p53 from degradation, linking the adaptor to genome-stability signaling.\",\n      \"evidence\": \"Tricomplex Co-IP, ubiquitination and p53 stability assays, domain mapping in breast cancer cells\",\n      \"pmids\": [\"18172499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of tricomplex formation not yet resolved\", \"Relationship to Numb's endocytic role unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined post-endocytic sorting as the route of Notch1 degradation, showing Numb directs Notch1 to late endosomes whereas its depletion favors recycling, dependent on Itch and endocytic motifs.\",\n      \"evidence\": \"Endosomal trafficking microscopy, Numb gain/loss-of-function, domain mutants, Itch Co-IP\",\n      \"pmids\": [\"19567869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sorting machinery directing late-endosomal targeting not fully identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked Numb to epithelial integrity by showing it binds E-cadherin and Par3, and that an aPKC/Par6 switch redirects Numb to control junction stability and migration.\",\n      \"evidence\": \"Co-IP, shRNA, confocal microscopy, scattering assays in MDCK cells\",\n      \"pmids\": [\"19609305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of E-cadherin regulation not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed Numb suppresses Rac1-GTP accumulation to maintain E-cadherin junctions and limit HGF-induced scattering, establishing a link to small-GTPase-driven motility.\",\n      \"evidence\": \"shRNA, Rac1-GTP pull-down, Rac1-inhibitor rescue, scattering assay\",\n      \"pmids\": [\"21147098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular connection between Numb and Rac1 regulation not defined here (single lab)\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Detailed how aPKC phosphorylation inhibits Numb binding to p120-catenin and alpha-adaptin to attenuate E-cadherin endocytosis, and showed receptor-specific Notch regulation (Notch1 but not Notch3).\",\n      \"evidence\": \"Co-IP, RNAi, phosphomimetic/binding-deficient mutants, kinase and internalization assays; reporter and ubiquitination assays for Notch isoforms\",\n      \"pmids\": [\"21775625\", \"21356309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Notch receptor selectivity not resolved\", \"Notch3 finding medium-confidence single-lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided the mechanistic basis of p53 protection by showing NUMB occupies both MDM2 substrate-binding surfaces via a single PTB region, disrupting MDM2-p53 and inhibiting p53 ubiquitination.\",\n      \"evidence\": \"In vitro binding, ubiquitination, domain deletion and point mutants, Co-IP\",\n      \"pmids\": [\"22337874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the assembled tricomplex not determined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Implicated Numb in mitotic fidelity by showing it cycles with and stabilizes Plk1 for proper spindle-pole localization, with loss causing G2/M arrest.\",\n      \"evidence\": \"Co-IP, colocalization, siRNA, cell-cycle and spindle-pole immunofluorescence in melanoma cells\",\n      \"pmids\": [\"22593191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect effect on Plk1 stability not resolved\", \"Single-lab, single set of methods\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that Numb prevents p53-dependent oxidative-stress senescence in muscle stem cells, placing Numb genetically upstream of p53 in tissue regeneration.\",\n      \"evidence\": \"Conditional Numb KO, antioxidant and p53-ablation rescue, senescence assays\",\n      \"pmids\": [\"26503169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between Numb loss and oxidative stress not fully defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Expanded Numb cargo control to VEGF receptors, showing it sustains VEGFR2/3 by promoting recycling, and identified MAPK/ERK-driven alternative splicing as a regulator of Numb isoform identity.\",\n      \"evidence\": \"Co-IP, recycling/degradation assays, endothelial inducible KO; splicing reporter, splicing-factor RNAi, ERK pathway manipulation\",\n      \"pmids\": [\"26069237\", \"27041567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants choosing degradation (ERBB2/Notch) vs recycling (VEGFR) fate unclear\", \"Splicing finding medium-confidence single-lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed in vivo that NUMB/NUMBL route ERBB2 to Rab7-dependent late-endosomal degradation to restrain proliferation, and that Plk1 phosphorylates Numb to trigger its degradation and antagonize p53 during DNA damage.\",\n      \"evidence\": \"Cardiac double KO, endosomal fractionation, Rab7 Co-IP, genetic rescue; in vitro Plk1 kinase assay, phospho-mutants, doxorubicin sensitivity and xenografts\",\n      \"pmids\": [\"28067668\", \"29059161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of ERBB2/YAP axis with Numb's other Hippo functions not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the biophysical mechanism of basal Numb localization (multivalent PTB-Pon phase separation), and uncovered NUMB-EFA6B-ARF6 control of Rac1 recycling and a role in mitochondrial fission via Drp1/ROCK.\",\n      \"evidence\": \"Structural analysis and in vitro phase separation with mutagenesis and Drosophila imaging; in vitro GEF assay, Co-IP, migration assays; conditional KO with phospho-Drp1 and pharmacological rescue\",\n      \"pmids\": [\"29467404\", \"30061108\", \"29890853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phase separation occurs in mammalian cortical asymmetry untested\", \"Drp1/ROCK finding medium-confidence single-lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reported a context-dependent reversal in which NUMB stabilizes N1ICD by recruiting BAP1, independent of its endocytic role, challenging the canonical Notch-inhibitory model.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, BAP1 catalytic mutant, N1ICD stability in cortical neural progenitors\",\n      \"pmids\": [\"31504682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contradicts established Notch-inhibitory role; reconciliation not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected Numb to neuronal proteostasis and to mitophagy-linked metabolic reprogramming, identifying Tau-level regulation and a Numb/Parkin axis controlling lineage plasticity.\",\n      \"evidence\": \"Conditional Numb KO and isoform overexpression in neurons with TauP301S cross; Numb-Parkin Co-IP, mitophagy and metabolomic/lactylation assays in tumor lines\",\n      \"pmids\": [\"36260685\", \"36724072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Numb lowers Tau not defined\", \"Numb-Parkin finding medium-confidence single-lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a density-sensing role in which phospho-SPTAN1 recruits long NUMB isoforms to membrane to sequester MARK kinases, activating Hippo/MST1-2 to suppress YAP for contact inhibition.\",\n      \"evidence\": \"Co-IP, isoform-specific and liver-specific KO, phospho-SPTAN1 and Hippo kinase activity assays\",\n      \"pmids\": [\"37843276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MARK sequestration not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Localized Numb to the ciliary pocket as a clathrin adaptor exporting Ptch1 from the cilium, defining a positive role in Hedgehog signaling and neural progenitor differentiation.\",\n      \"evidence\": \"Proximity proteomics, live imaging of Ptch1 ciliary exit, cerebellar conditional KO, differentiation assays\",\n      \"pmids\": [\"38664376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Numb selectively targets ciliary-pocket cargo unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single adaptor selects between opposing post-endocytic fates (degradation versus recycling) for different cargoes and how its endocytic, p53-protective, and Hippo-regulatory activities are integrated within one cell.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking cargo identity to sorting outcome\", \"Structural basis of the p53-MDM2 tricomplex not solved\", \"Conditions favoring Notch inhibition vs N1ICD stabilization not reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 7, 9, 23]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [1, 7, 15, 23, 27]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 8, 12, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 2, 6, 23]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 10, 11, 25]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [6, 9, 15]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 2, 7, 9, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 23, 24, 27]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 15, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 4, 8, 12, 19]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 28, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NOTCH1\", \"ITCH\", \"MDM2\", \"TP53\", \"AP2A (alpha-adaptin)\", \"RAB7\", \"VEGFR2\", \"SPTAN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}