NUMB

Summary

NUMB (NUMB endocytic adaptor protein, HGNC:8060) is a protein-coding gene on chromosome 14q24.3, encoding Protein numb homolog (P49757). Regulates clathrin-mediated receptor endocytosis.

The protein encoded by this gene plays a role in the determination of cell fates during development. The encoded protein, whose degradation is induced in a proteasome-dependent manner by MDM2, is a membrane-bound protein that has been shown to associate with EPS15, LNX1, and NOTCH1. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 8650 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 92 total
• MANE Select transcript: NM_001005743

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8060
Approved symbol	NUMB
Name	NUMB endocytic adaptor protein
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000133961
Ensembl biotype	protein_coding
OMIM	603728
Entrez	8650

Gene structure

Transcript identifiers

Ensembl transcripts: 155 — 139 protein_coding, 10 protein_coding_CDS_not_defined, 6 retained_intron

ENST00000355058, ENST00000356296, ENST00000359560, ENST00000535282, ENST00000544991, ENST00000553415, ENST00000553997, ENST00000554014, ENST00000554315, ENST00000554394, ENST00000554521, ENST00000554546, ENST00000554818, ENST00000555238, ENST00000555307, ENST00000555394, ENST00000555738, ENST00000555859, ENST00000555987, ENST00000556112, ENST00000556600, ENST00000556700, ENST00000556772, ENST00000556989, ENST00000557031, ENST00000557486, ENST00000557577, ENST00000557581, ENST00000557597, ENST00000557774, ENST00000559312, ENST00000560335, ENST00000643731, ENST00000646944, ENST00000647202, ENST00000863595, ENST00000863596, ENST00000863597, ENST00000863598, ENST00000863599, ENST00000863600, ENST00000863601, ENST00000863602, ENST00000863603, ENST00000863604, ENST00000863605, ENST00000863606, ENST00000863607, ENST00000863608, ENST00000863609, ENST00000863610, ENST00000863611, ENST00000863612, ENST00000863613, ENST00000863614, ENST00000863615, ENST00000863616, ENST00000863617, ENST00000863618, ENST00000863619, ENST00000863620, ENST00000863621, ENST00000863622, ENST00000863623, ENST00000863624, ENST00000863625, ENST00000863626, ENST00000863627, ENST00000863628, ENST00000863629, ENST00000863630, ENST00000863631, ENST00000863632, ENST00000863633, ENST00000863634, ENST00000863635, ENST00000863636, ENST00000863637, ENST00000863638, ENST00000863639, ENST00000863640, ENST00000863641, ENST00000863642, ENST00000863643, ENST00000863644, ENST00000863645, ENST00000863646, ENST00000863647, ENST00000863648, ENST00000863649, ENST00000863650, ENST00000863651, ENST00000863652, ENST00000863653, ENST00000863655, ENST00000863656, ENST00000863657, ENST00000863661, ENST00000863662, ENST00000863663, ENST00000863664, ENST00000863665, ENST00000863666, ENST00000863667, ENST00000863668, ENST00000863669, ENST00000863670, ENST00000863671, ENST00000863672, ENST00000925283, ENST00000925284, ENST00000925285, ENST00000925286, ENST00000925287, ENST00000925288, ENST00000925289, ENST00000925290, ENST00000925291, ENST00000925292, ENST00000925293, ENST00000925294, ENST00000925295, ENST00000925296, ENST00000957445, ENST00000957446, ENST00000957447, ENST00000957448, ENST00000957449, ENST00000957450, ENST00000957451, ENST00000957452, ENST00000957453, ENST00000957454, ENST00000957455, ENST00000957456, ENST00000957457, ENST00000957458, ENST00000957459, ENST00000957460, ENST00000957461, ENST00000957462, ENST00000957463, ENST00000957464, ENST00000957465, ENST00000957466, ENST00000957467, ENST00000957468, ENST00000957469, ENST00000957470, ENST00000957471, ENST00000957472, ENST00000957473, ENST00000957474, ENST00000957475, ENST00000957476

RefSeq mRNA: 5 — MANE Select: NM_001005743 NM_001005743, NM_001005744, NM_001005745, NM_001320114, NM_003744

CCDS: CCDS32115, CCDS32116, CCDS55927, CCDS9814

Canonical transcript exons

ENST00000555238 — 13 exons

Exon	Start	End
ENSE00001689532	73279281	73279424
ENSE00002228686	73458493	73458546
ENSE00002505332	73275216	73277293
ENSE00003495034	73297211	73297285
ENSE00003573756	73282359	73282505
ENSE00003612959	73316390	73316422
ENSE00003626002	73292734	73292874
ENSE00003633138	73287110	73287314
ENSE00003635053	73355626	73355766
ENSE00003662648	73284081	73284374
ENSE00003791033	73323130	73323204
ENSE00003828472	73366897	73366981
ENSE00003830790	73409937	73410068

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 97.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 42.9683 / max 884.4999, expressed in 1818 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143962	41.4991	1817
143961	1.2859	495
143958	0.1315	39
143959	0.0518	6

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	97.49	gold quality
colonic epithelium	UBERON:0000397	97.29	gold quality
mononuclear cell	CL:0000842	96.92	gold quality
leukocyte	CL:0000738	96.81	gold quality
right lung	UBERON:0002167	96.68	gold quality
blood	UBERON:0000178	96.17	gold quality
gall bladder	UBERON:0002110	95.85	gold quality
right uterine tube	UBERON:0001302	95.74	gold quality
stromal cell of endometrium	CL:0002255	95.69	gold quality
rectum	UBERON:0001052	95.66	gold quality
oocyte	CL:0000023	95.64	gold quality
sural nerve	UBERON:0015488	95.32	gold quality
upper lobe of left lung	UBERON:0008952	95.27	gold quality
secondary oocyte	CL:0000655	94.90	gold quality
minor salivary gland	UBERON:0001830	94.64	gold quality
metanephros cortex	UBERON:0010533	94.58	gold quality
buccal mucosa cell	CL:0002336	94.56	gold quality
left uterine tube	UBERON:0001303	94.54	gold quality
body of uterus	UBERON:0009853	94.52	gold quality
lower esophagus	UBERON:0013473	94.44	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.44	gold quality
upper lobe of lung	UBERON:0008948	94.42	gold quality
transverse colon	UBERON:0001157	94.37	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.30	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.12	gold quality
tibial nerve	UBERON:0001323	94.01	gold quality
body of pancreas	UBERON:0001150	94.00	gold quality
lower esophagus mucosa	UBERON:0035834	93.92	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.88	gold quality
right lobe of thyroid gland	UBERON:0001119	93.87	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-135	no	901.08
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HES1, HNF4A, KLF8, MSI2, SATB1

miRNA regulators (miRDB)

141 targeting NUMB, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515

Literature-anchored findings (GeneRIF, showing 40)

• These data strongly suggest that Mdm2 functions as the ubiquitin ligase toward hNumb and that it induces its degradation in intact cells. (PMID:12646252)
• the Numb/Notch biological antagonism has a role in homeostasis of the normal mammary parenchyma and its subversion contributes to human mammary carcinogenesis (PMID:15492044)
• These results highlight a role of Numb for dendritic spine development and synaptic functions with intersectin and EphB2. (PMID:16394100)
• The two distinct types of hNumb isoforms could contribute to different phases of neurogenesis in the embryonic CNS. (PMID:16508311)
• Epigenetic silencing, deletion and loss-of-function mutation of NUMB gene could lead to carcinogenesis through the dysregulation of the WNT - Notch signaling cycle. (PMID:16865239)
• Hedgehog transcription factor Gli1 is targeted by Numb for Itch-dependent ubiquitination, which suppresses Hedgehog signals, thus arresting growth and promoting cell differentiation. (PMID:17115028)
• significantly lower expressions of Notch1, Jagged1, Numb, and Delta-like 1 were evident in muscle biopsies from older men (60-75 years old) compared to muscle from younger men (18-25 years old). (PMID:17301032)
• Because Numb interacts with the aPKC binding partner PAR-3, we propose a model in which polarized Numb phosphorylation contributes to cell migration by directing integrin endocytosis to the leading edge (PMID:17609107)
• NUMB enters in a tricomplex with p53 and the E3 ubiquitin ligase HDM2 (also known as MDM2), thereby preventing ubiquitination and degradation of p53 (PMID:18172499)
• Numb is implicated in aberrant differentiation programs of salivary gland carcinomas (PMID:18179751)
• Numb expression in astrocytomas recapitulates that of progenitor cells during neurodevelopment, and suggests a role for Numb in astrocytoma oncogenesis. (PMID:18384513)
• Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoform-dependent manner and have roles in Alzheimer disease pathogenesis (PMID:18599481)
• These observations demonstrate that Numb3 is an endocytic receptor for P-selectin and may be responsible for the rapid internalization of P-selectin when endothelial activation ends. (PMID:19138666)
• Numb promotes neuronal differentiation by a mechanism involving PTB domain-specific regulation of Ca2+ influx and MAP kinase activation. (PMID:19344753)
• Expression of Numb protein in Cervical squamous epithelia may be among the mechanisms involved in the genesis of cervical squamous cell carcinomas (PMID:19468255)
• Results indicate that loss of Numb expression is a marker of tumor aggressiveness, potentially linked to BRCA1 status and a cancer stem cell phenotype in primary breast cancer. (PMID:19795205)
• Numb activates the catalytic activity of Itch, releasing it from an inhibitory intramolecular interaction between its homologous to E6-AP C-terminus and WW domains. (PMID:20818436)
• we report the identification ofthe novel isoforms, NUMB5 and NUMB6, and propose a link between the expression of these isoforms and cancer (PMID:21122105)
• cell migration studies revealed NUMB isoform 1 to be involved in EVT cell migration and NUMB isoforms 2 and 4 to induce EVT apoptosis (PMID:21486681)
• atypical protein kinase C phosphorylates Numb to prevent its binding to p120 and alpha-adaptin, thereby attenuating E-cadherin endocytosis to maintain apicobasal polarity (PMID:21775625)
• NUMB is consistently expressed in glioma biopsies with predominance of NUMB2/4 isoforms as determined by isoform-specific real-time PCR and Western blotting. (PMID:21939656)
• analysis of MDM2 protein-mediated ubiquitination of numb protein (PMID:22337874)
• Numb has an important regulation in the process of colon cancer progression and may play a protective role against tumor development. (PMID:22455121)
• Numb regulates glioma stem cell fate and growth by altering epidermal growth factor receptor and Skp1-Cullin-F-box ubiquitin ligase activity (PMID:22553175)
• Dysregulation of Numb expression results in mislocalized Plk1 and poor centrosomal gamma-tubulin recruitment, potentially contributing to mitotic errors, aneuploidy, and cancer development. (PMID:22593191)
• This study implies that any mutations within the NUMB gene that might influence the disease course of chronic myeloid leukemia are very rare. (PMID:22734830)
• Down-modulation of NUMB is associated with myelodysplastic syndromes and acute myeloid leukemia. (PMID:22784712)
• Numb1 interacts with TRPV6 through charged residues and inhibits its activity via the regulation of protein expression. (PMID:23140583)
• Expression of stem cell regulator NUMB is not associated with any prognostic significance in acute myeloid leukemia patients. (PMID:23233047)
• Overexpression of Numb inhibited proliferation, promoted apoptosis and enhanced sensitivity to cisplatin, and activated caspase-9 and caspase-3 through release of cytochrome c as well as downregulation of XIAP and survivin. (PMID:23624653)
• Data indicate the Set8-Numb-p53 signaling axis as an important regulatory pathway for apoptosis and suggests a therapeutic strategy by targeting Numb methylation. (PMID:23706821)
• The Numb modulates the paracellular permeability by affecting apical junctional complex (AJC) assembly and myosin light chain (MLC) phosphorylation. (PMID:23872314)
• The study demonstrates coordinated regulation of Numb, MDM2 and p53 on cell invasion and migration in pancreatic cancer. (PMID:23881403)
• miR-146a enhances the oncogenicity of oral carcinoma by concomitant targeting of the IRAK1, TRAF6 and NUMB genes. (PMID:24302991)
• Identify the Notch pathway regulator NUMB as a key target of these factors. (PMID:24332178)
• Numb up-regulation significantly correlates with cell proliferation and poor prognosis in hepatocellular carcinoma patients. (PMID:24770339)
• Findings suggested NUMB-1 functions as a tumor-suppressor and serves as a prognositc biomarker for ESCC patients. (PMID:24980814)
• Numb specifically regulates NPC1L1-mediated cholesterol absorption both in human intestine and liver, distinct from ARH and Dab2, which selectively participate in LDLR-mediated LDL uptake. (PMID:25331956)
• Using LC-MS/MS, the study reports the identification of 25 serine/threonine Numb phosphorylation sites, and a single tyrosine phosphorylation site. (PMID:25403733)
• Taken together, our data suggest that Numb may possibly function as a tumor suppressor involved in the carcinogenesis of clear cell renal cell carcinoma (PMID:25480416)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	numb	ENSDARG00000027279
mus_musculus	Numb	ENSMUSG00000021224
rattus_norvegicus	Numb	ENSRNOG00000009653
drosophila_melanogaster	numb	FBGN0002973
drosophila_melanogaster	CG8312	FBGN0037720
caenorhabditis_elegans		WBGENE00003830
caenorhabditis_elegans		WBGENE00009930

Paralogs (11): MAPK8IP2 (ENSG00000008735), NUMBL (ENSG00000105245), MAPK8IP1 (ENSG00000121653), GULP1 (ENSG00000144366), DAB2 (ENSG00000153071), LDLRAP1 (ENSG00000157978), DAB1 (ENSG00000173406), FAM43B (ENSG00000183114), FAM43A (ENSG00000185112), NOS1AP (ENSG00000198929), C1orf226 (ENSG00000239887)

Protein

Protein identifiers

Protein numb homolog — P49757 (reviewed: P49757)

Alternative names: Protein S171

All UniProt accessions (6): P49757, G3V3M5, G3V3R1, G3V3Z8, G3V433, G3V4S6

UniProt curated annotations — full annotation on UniProt →

Function. Regulates clathrin-mediated receptor endocytosis. Plays a role in the process of neurogenesis. 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. 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. May also mediate local repair of brain ventricular wall damage.

Subunit / interactions. Interacts with SIAH1. Interacts with LNX. Interacts with CDH1. Interacts with TFAP2A and TFAP2B. Interacts with RALBP1 in a complex also containing EPN1 and TFAP2A during interphase and mitosis. Interacts with AAK1. May interact with DUOXA1.

Subcellular location. Cell membrane. Endosome membrane.

Post-translational modifications. Phosphorylated on Ser-276 and Ser-295 by CaMK1. Isoform 1 and isoform 2 are ubiquitinated by LNX leading to their subsequent proteasomal degradation. Ubiquitinated; mediated by SIAH1 and leading to its subsequent proteasomal degradation.

Isoforms (9)

UniProt ID	Names	Canonical?
P49757-1	1, p72	yes
P49757-2	2, p66
P49757-3	3, p71
P49757-4	4, p65
P49757-5	5
P49757-6	6
P49757-7	7
P49757-8	8
P49757-9	9

RefSeq proteins (5): NP_001005743, NP_001005744, NP_001005745, NP_001307043, NP_003735 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006020	PTB/PI_dom	Domain
IPR010449	Numb_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR016698	Numb/numb-like	Family

Pfam: PF00640, PF06311

UniProt features (48 total): modified residue 10, strand 8, splice variant 5, sequence conflict 5, helix 5, compositionally biased region 4, region of interest 3, turn 3, sequence variant 2, chain 1, domain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5NJJ	X-RAY DIFFRACTION	2.7
5NJK	X-RAY DIFFRACTION	3.13

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49757-F1	60.47	0.19

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (10): 194, 243, 244, 276, 295, 425, 436, 438, 634, 102

Mutagenesis-validated functional residues (1):

Position	Phenotype
102	loss of aak1-mediated phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-437239	Recycling pathway of L1
R-HSA-5610780	Degradation of GLI1 by the proteasome
R-HSA-5632684	Hedgehog ‘on’ state
R-HSA-9725554	Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin

MSigDB gene sets: 292 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, REACTOME_SIGNALING_BY_NOTCH, TGCGCANK_UNKNOWN, MORF_ATRX, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, TATTATA_MIR374, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, TACAATC_MIR508, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_VENTRICULAR_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_CELL_PROLIFERATION_IN_FOREBRAIN, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY

GO Biological Process (12): axonogenesis (GO:0007409), lateral ventricle development (GO:0021670), neuroblast division in subventricular zone (GO:0021849), regulation of endocytosis (GO:0030100), positive regulation of cell migration (GO:0030335), adherens junction organization (GO:0034332), positive regulation of neurogenesis (GO:0050769), regulation of postsynaptic neurotransmitter receptor internalization (GO:0099149), negative regulation of protein localization to plasma membrane (GO:1903077), nervous system development (GO:0007399), neuroblast proliferation (GO:0007405), forebrain development (GO:0030900)

GO Molecular Function (4): beta-catenin binding (GO:0008013), alpha-catenin binding (GO:0045294), cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (13): cytoplasm (GO:0005737), early endosome (GO:0005769), plasma membrane (GO:0005886), clathrin-coated pit (GO:0005905), focal adhesion (GO:0005925), endosome membrane (GO:0010008), basolateral plasma membrane (GO:0016323), clathrin-coated vesicle (GO:0030136), cytoplasmic vesicle (GO:0031410), apical part of cell (GO:0045177), glutamatergic synapse (GO:0098978), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signaling by NOTCH1	1
L1CAM interactions	1
Hedgehog ‘off’ state	1
Signaling by Hedgehog	1
Developmental Cell Lineages of the Integumentary System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
anatomical structure development	2
protein binding	2
endosome	2
membrane	2
endomembrane system	2
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
telencephalon development	1
ventricular system development	1
cell proliferation in forebrain	1
neuroblast division	1
endocytosis	1
regulation of cellular component organization	1
regulation of vesicle-mediated transport	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
cell-cell junction organization	1
positive regulation of cell development	1
neurogenesis	1
regulation of neurogenesis	1
positive regulation of nervous system development	1
regulation of receptor internalization	1
regulation of biological quality	1
postsynaptic neurotransmitter receptor internalization	1
protein localization to plasma membrane	1
regulation of protein localization to plasma membrane	1
negative regulation of protein localization to cell periphery	1
negative regulation of protein localization to membrane	1
system development	1
generation of neurons	1
neural precursor cell proliferation	1
brain development	1
cell adhesion molecule binding	1
binding	1
intracellular anatomical structure	1
cell periphery	1
cell-substrate junction	1

Protein interactions and networks

STRING

2410 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NUMB	MDM2	Q00987	990
NUMB	LNX1	Q8TBB1	980
NUMB	EPS15	P42566	973
NUMB	DPYSL2	Q16555	946
NUMB	MSI2	Q96DH6	930
NUMB	LNX2	Q8N448	878
NUMB	CDH1	P12830	860
NUMB	NOTCH1	P46531	849
NUMB	ITCH	Q96J02	815
NUMB	MSI1	O43347	799
NUMB	JAG1	P78504	753
NUMB	NOTCH2	Q04721	738
NUMB	CDH17	Q12864	733
NUMB	SH3BP4	Q9P0V3	726
NUMB	PARD3	Q8TEW0	712

IntAct

128 interactions, top by confidence:

A	B	Type	Score
MDM2	TP53	psi-mi:“MI:0914”(association)	1.000
MDM2	TP53	psi-mi:“MI:0915”(physical association)	1.000
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
EPS15	NUMB	psi-mi:“MI:0407”(direct interaction)	0.750
EPS15	NUMB	psi-mi:“MI:0915”(physical association)	0.750
KBTBD7	METTL15	psi-mi:“MI:0914”(association)	0.730
MDM2	NUMB	psi-mi:“MI:0915”(physical association)	0.720
MDM2	NUMB	psi-mi:“MI:0407”(direct interaction)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
STAMBPL1	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
NUMB	SLC1A1	psi-mi:“MI:0914”(association)	0.640
SLC1A1	AGPAT2	psi-mi:“MI:0914”(association)	0.640
SNX9	WASL	psi-mi:“MI:0914”(association)	0.640
NUMB	TP53	psi-mi:“MI:0914”(association)	0.630
TP53	NUMB	psi-mi:“MI:0407”(direct interaction)	0.630
TP53	NUMB	psi-mi:“MI:0914”(association)	0.630
NUMB	TP53	psi-mi:“MI:0407”(direct interaction)	0.630
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570

BioGRID (363): NUMB (Affinity Capture-MS), NUMB (Two-hybrid), OLIG1 (Two-hybrid), NUMB (Two-hybrid), LNX2 (Two-hybrid), NUMB (Two-hybrid), TERF2 (Two-hybrid), NUMB (Proximity Label-MS), NUMB (Affinity Capture-MS), NUMB (Affinity Capture-MS), NUMB (Affinity Capture-MS), NUMB (Affinity Capture-MS), NUMB (Affinity Capture-MS), NUMB (Affinity Capture-MS), NUMB (Affinity Capture-MS)

ESM2 similar proteins: A1L1I3, A5PKW4, O08919, O70405, O75385, O75420, O75553, P16554, P42128, P49757, P53814, P85037, P97318, P98081, Q04637, Q2LC84, Q3UCQ1, Q4KMP7, Q5DTT2, Q5I1X5, Q5RBR0, Q5VZ18, Q69ZH9, Q69ZI1, Q7TN02, Q7Z6J0, Q80VC9, Q80XI3, Q80Z38, Q86V15, Q8BGT6, Q8BHL3, Q8BSD5, Q8C120, Q8CI12, Q8IY33, Q8K4J6, Q8N3F8, Q8TEH3, Q8TEJ3

Diamond homologs: A1L1I3, O08919, O88797, P16554, P49757, P98078, P98081, P98082, Q2LC84, Q5PQS4, Q5SW96, Q801G1, Q8C142, Q8K2A1, Q9QZS3, Q9UBP9, Q9XTY6, Q9Y6R0, O75553, P97318, Q8CJH2, Q9BGX5, Q67FQ3, A5PMU4, D3ZAR1, Q32PV0, P0C6S7, Q8BIZ1

SIGNOR signaling

21 interactions.

A	Effect	B	Mechanism
LNX1	down-regulates	NUMB	ubiquitination
SIAH1	down-regulates	NUMB	ubiquitination
SLC30A9	“down-regulates quantity by destabilization”	NUMB	ubiquitination
CAMK1	down-regulates	NUMB	phosphorylation
PRKCI	down-regulates	NUMB	phosphorylation
MSI1	down-regulates	NUMB	binding
NUMB	down-regulates	GLI1	binding
NUMB	up-regulates	ITCH	binding
NUMB	down-regulates	MDM2	binding
NUMB	up-regulates	TP53
MSI2	“down-regulates quantity by repression”	NUMB	“transcriptional regulation”
NUMB	up-regulates	TP53	binding
AAK1	up-regulates	NUMB	phosphorylation
AAK1	unknown	NUMB	phosphorylation
SATB1	“down-regulates quantity by repression”	NUMB	“transcriptional regulation”
LNX2	“down-regulates quantity by destabilization”	NUMB	ubiquitination
MDM2	down-regulates	NUMB	ubiquitination
NUMB	“down-regulates quantity by destabilization”	NOTCH1	ubiquitination
NUMB	down-regulates	NOTCH
LNX2	“down-regulates quantity by destabilization”	NUMB	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 127 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	8	51.2×	2e-10
Activation of BAD and translocation to mitochondria	7	50.8×	3e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	44.8×	7e-09
WNT5A-dependent internalization of FZD4	6	43.5×	2e-07
VLDLR internalisation and degradation	5	34.0×	8e-06
Activation of BH3-only proteins	7	33.1×	7e-08
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	5	30.2×	1e-05
The role of Nef in HIV-1 replication and disease pathogenesis	5	30.2×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
clathrin coat assembly	7	54.5×	3e-08
clathrin-dependent endocytosis	7	35.7×	3e-07
synaptic vesicle endocytosis	7	26.5×	2e-06
protein targeting	5	16.1×	2e-03
insulin receptor signaling pathway	6	11.7×	2e-03
epidermal growth factor receptor signaling pathway	5	10.9×	8e-03
cell surface receptor protein tyrosine kinase signaling pathway	6	9.1×	6e-03
intracellular protein localization	8	7.3×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

92 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	73
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1726 predictions. Top by Δscore:

Variant	Effect	Δscore
14:73277291:TCCC:T	acceptor_loss	1.0000
14:73277292:CCCT:C	acceptor_loss	1.0000
14:73277294:CTGG:C	acceptor_loss	1.0000
14:73277302:A:T	acceptor_gain	1.0000
14:73282506:C:CC	acceptor_gain	1.0000
14:73284288:C:CT	acceptor_gain	1.0000
14:73284378:A:T	acceptor_gain	1.0000
14:73287109:CCTTT:C	donor_gain	1.0000
14:73292732:A:AC	donor_gain	1.0000
14:73292733:C:CC	donor_gain	1.0000
14:73323128:A:AC	donor_gain	1.0000
14:73323128:ACAG:A	donor_gain	1.0000
14:73323129:C:CC	donor_gain	1.0000
14:73323129:CAG:C	donor_gain	1.0000
14:73323129:CAGC:C	donor_gain	1.0000
14:73323201:GGTA:G	acceptor_gain	1.0000
14:73323205:C:CC	acceptor_gain	1.0000
14:73355622:TTAC:T	donor_loss	1.0000
14:73355623:TACC:T	donor_loss	1.0000
14:73355624:A:AC	donor_gain	1.0000
14:73355624:A:AT	donor_loss	1.0000
14:73355625:C:CC	donor_gain	1.0000
14:73355625:CCT:C	donor_gain	1.0000
14:73355627:TTA:T	donor_gain	1.0000
14:73277292:CC:C	acceptor_gain	0.9900
14:73277293:CC:C	acceptor_gain	0.9900
14:73277294:C:CC	acceptor_gain	0.9900
14:73277295:T:A	acceptor_loss	0.9900
14:73277301:C:CT	acceptor_gain	0.9900
14:73277304:C:CT	acceptor_gain	0.9900

AlphaMissense

4255 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:73277205:C:A	W443C	1.000
14:73277205:C:G	W443C	1.000
14:73277207:A:G	W443R	1.000
14:73277207:A:T	W443R	1.000
14:73284143:A:G	L296P	1.000
14:73284160:A:C	F290L	1.000
14:73284160:A:T	F290L	1.000
14:73284161:A:C	F290C	1.000
14:73284161:A:G	F290S	1.000
14:73284162:A:G	F290L	1.000
14:73284213:G:T	R273S	1.000
14:73284243:G:T	R263S	1.000
14:73287180:G:C	F195L	1.000
14:73287180:G:T	F195L	1.000
14:73287181:A:G	F195S	1.000
14:73287182:A:G	F195L	1.000
14:73287187:C:T	G193E	1.000
14:73287188:C:G	G193R	1.000
14:73287188:C:T	G193R	1.000
14:73287192:T:A	R191S	1.000
14:73287192:T:G	R191S	1.000
14:73287193:C:A	R191I	1.000
14:73287193:C:G	R191T	1.000
14:73287198:A:C	F189L	1.000
14:73287198:A:T	F189L	1.000
14:73287199:A:C	F189C	1.000
14:73287199:A:G	F189S	1.000
14:73287200:A:G	F189L	1.000
14:73287226:G:T	A180D	1.000
14:73287250:C:G	R172P	1.000

dbSNP variants (sampled 300 via entrez): RS1000007981 (14:73374886 A>G), RS1000008500 (14:73323018 T>A,C), RS1000041711 (14:73369043 T>C), RS1000062392 (14:73278153 G>A), RS1000092657 (14:73413147 T>A,C), RS1000102325 (14:73373063 C>T), RS1000149215 (14:73351992 T>A), RS1000154422 (14:73416484 G>A), RS1000188209 (14:73439754 T>C), RS1000208294 (14:73297755 C>T), RS1000217904 (14:73440091 A>G), RS1000237967 (14:73298067 C>G,T), RS1000262902 (14:73345243 G>A), RS1000271361 (14:73318746 G>A), RS1000311896 (14:73309125 G>A)

Disease associations

OMIM: gene MIM:603728 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000097_2	Coronary artery calcification	6.000000e-06
GCST001715_4	Bipolar disorder with mood-incongruent psychosis	7.000000e-07
GCST006976_61	Macular thickness	4.000000e-10
GCST008512_32	Multisite chronic pain	4.000000e-08
GCST011954_5	White matter hyperintensity volume x hypertension interaction (2df)	3.000000e-08
GCST012332_40	Multisite chronic pain	5.000000e-08
GCST90002384_368	Hemoglobin	7.000000e-15

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0010100	multisite chronic pain
EFO:0005665	white matter hyperintensity measurement
EFO:0004509	hemoglobin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

49 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment, decreases expression	2
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Ozone	increases oxidation, increases abundance, affects cotreatment, decreases expression	2
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment, decreases expression	1
bisphenol A	decreases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
coumarin	increases phosphorylation	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene	affects cotreatment, increases expression	1
N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
bisphenol B	increases expression	1
bisphenol S	decreases methylation	1
bisphenol AF	increases expression	1
Bortezomib	increases expression	1
Temozolomide	decreases expression	1
Arsenic Trioxide	decreases expression	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Air Pollutants	increases oxidation, affects cotreatment, decreases expression, increases abundance	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	decreases expression	1
Caffeine	affects phosphorylation	1
Cisplatin	decreases expression	1
Demecolcine	increases expression	1

Cellosaurus cell lines

8 cell lines: 7 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7W8	Ubigene A-549 NUMB KO	Cancer cell line	Male
CVCL_D8RR	Ubigene HCT 116 NUMB KO	Cancer cell line	Male
CVCL_D9LS	Ubigene HEK293 NUMB KO	Transformed cell line	Female
CVCL_E0JE	Ubigene HeLa NUMB KO	Cancer cell line	Female
CVCL_F1M8	HyCyte A-549 KO-hNUMB	Cancer cell line	Male
CVCL_TB46	HAP1 NUMB (-) 1	Cancer cell line	Male
CVCL_XR24	HAP1 NUMB (-) 2	Cancer cell line	Male
CVCL_XR25	HAP1 NUMB (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.