NOTCH2NLB

Summary

NOTCH2NLB (notch 2 N-terminal like B, HGNC:53923) is a protein-coding gene on chromosome 1q21.2, encoding Notch homolog 2 N-terminal-like protein B (P0DPK3). Human-specific protein that promotes neural progenitor proliferation and evolutionary expansion of the brain neocortex by regulating the Notch signaling pathway.

Enables Notch binding activity. Involved in cerebral cortex development and positive regulation of Notch signaling pathway. Located in extracellular region.

Source: NCBI Gene 100996763 — RefSeq curated summary.

At a glance

• MANE Select transcript: NM_001364008

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:53923
Approved symbol	NOTCH2NLB
Name	notch 2 N-terminal like B
Location	1q21.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000286019
Ensembl biotype	protein_coding
OMIM	618024
Entrez	100996763

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000593495, ENST00000850899, ENST00000913101

RefSeq mRNA: 3 — MANE Select: NM_001364008 NM_001364007, NM_001364008, NM_001395234

CCDS: CCDS86012

Canonical transcript exons

ENST00000593495 — 5 exons

Exon	Start	End
ENSE00003734113	148607410	148607745
ENSE00003746974	148615691	148615950
ENSE00003978160	148600285	148607159
ENSE00004282656	148640016	148640089
ENSE00004282657	148679462	148679746

Expression profiles

Bgee: expression breadth ubiquitous, 132 present calls, max score 87.58.

FANTOM5 (CAGE): breadth broad, TPM avg 0.8998 / max 41.9765, expressed in 469 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
201701	0.8998	469

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.58	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.22	gold quality
stromal cell of endometrium	CL:0002255	85.92	gold quality
left testis	UBERON:0004533	82.75	gold quality
testis	UBERON:0000473	81.66	gold quality
right testis	UBERON:0004534	81.09	gold quality
lower esophagus mucosa	UBERON:0035834	79.98	gold quality
skin of leg	UBERON:0001511	79.94	gold quality
skin of abdomen	UBERON:0001416	79.89	gold quality
zone of skin	UBERON:0000014	79.63	gold quality
monocyte	CL:0000576	79.26	gold quality
ascending aorta	UBERON:0001496	78.89	gold quality
leukocyte	CL:0000738	78.73	gold quality
thoracic aorta	UBERON:0001515	78.19	gold quality
esophagus mucosa	UBERON:0002469	78.02	gold quality
vagina	UBERON:0000996	77.82	gold quality
popliteal artery	UBERON:0002250	77.25	gold quality
tibial artery	UBERON:0007610	77.24	gold quality
ectocervix	UBERON:0012249	77.23	gold quality
endocervix	UBERON:0000458	76.73	gold quality
blood	UBERON:0000178	76.51	gold quality
granulocyte	CL:0000094	75.53	gold quality
left coronary artery	UBERON:0001626	75.26	gold quality
tibial nerve	UBERON:0001323	75.02	gold quality
subcutaneous adipose tissue	UBERON:0002190	74.97	gold quality
mucosa of stomach	UBERON:0001199	74.92	gold quality
right lobe of liver	UBERON:0001114	74.55	gold quality
prostate gland	UBERON:0002367	74.49	gold quality
ventricular zone	UBERON:0003053	74.40	gold quality
uterine cervix	UBERON:0000002	74.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	13.59
E-ANND-3	yes	6.54

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 3)

• the emergence of human-specific NOTCH2NL genes may have contributed to the rapid evolution of the larger human neocortex, accompanied by loss of genomic stability at the 1q21.1 locus and resulting recurrent neurodevelopmental disorders (PMID:29856954)
• NOTCH2NL can expand human cortical progenitors and increase their neuronal output at the clonal level through cell-autonomous activation of the Notch pathway. (PMID:29856955)
• Evolution of Human Brain Size-Associated NOTCH2NL Genes Proceeds toward Reduced Protein Levels. (PMID:32330268)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	notchl	ENSDARG00000088308
drosophila_melanogaster	N	FBGN0004647
caenorhabditis_elegans		WBGENE00003001

Paralogs (7): NOTCH3 (ENSG00000074181), NOTCH2 (ENSG00000134250), NOTCH1 (ENSG00000148400), SNED1 (ENSG00000162804), NOTCH2NLA (ENSG00000264343), NOTCH2NLR (ENSG00000286106), NOTCH2NLC (ENSG00000286219)

Protein

Protein identifiers

Notch homolog 2 N-terminal-like protein B — P0DPK3 (reviewed: P0DPK3)

All UniProt accessions (1): P0DPK3

UniProt curated annotations — full annotation on UniProt →

Function. Human-specific protein that promotes neural progenitor proliferation and evolutionary expansion of the brain neocortex by regulating the Notch signaling pathway. Able to promote neural progenitor self-renewal, possibly by down-regulating neuronal differentiation genes, thereby delaying the differentiation of neuronal progenitors and leading to an overall final increase in neuronal production. Acts by enhancing the Notch signaling pathway via two different mechanisms that probably work in parallel to reach the same effect. Enhances Notch signaling pathway in a non-cell-autonomous manner via direct interaction with NOTCH2. Also promotes Notch signaling pathway in a cell-autonomous manner through inhibition of cis DLL1-NOTCH2 interactions, which promotes neuronal differentiation.

Subunit / interactions. Interacts with NOTCH2. Interacts with DLL1; the interaction is direct.

Subcellular location. Secreted.

Tissue specificity. Expressed in radial glia neural stem cells during cortical development.

Disease relevance. Defects in NOTCH2NLB may be a cause of chromosome 1q21.1 deletion/duplication syndrome. Deletions of NOTCH2NL (NOTCH2NLA, NOTCH2NLB and/or NOTCH2NLC) are present in patients affected by microcephaly, whereas macrocephaly is observed in patients with NOTCH2NL duplications.

Miscellaneous. NOTCH2NLA, NOTCH2NLB and NOTCH2NLC paralogs arose between 4 and 3 million years ago, after the separation of hominids from the chimpanzee and during the early stages of the expansion of the human cortex.

Similarity. Belongs to the NOTCH family.

Isoforms (2)

UniProt ID	Names	Canonical?
P0DPK3-1	1	yes
P0DPK3-2	2

RefSeq proteins (3): NP_001350936, NP_001350937, NP_001382163 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR049883	NOTCH1_EGF-like	Domain

Pfam: PF00008, PF07645

UniProt features (28 total): disulfide bond 17, domain 6, glycosylation site 2, signal peptide 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0DPK3-F1	84.73	0.70

Functional residue map

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

Disulfide bonds (17): 28–41, 35–51, 53–62, 68–79, 73–90, 92–101, 109–121, 115–131, 133–142, 148–159, 153–168, 170–179, 186–198, 192–207, 209–218, 225–236, 230–246

Glycosylation sites (2): 46, 155

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2979096	NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-9911233	Expression of NOTCH2NL genes

MSigDB gene sets: 19 (showing top): REACTOME_SIGNALING_BY_NOTCH, GOBP_POSITIVE_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_CEREBRAL_CORTEX_DEVELOPMENT, GOBP_PALLIUM_DEVELOPMENT, GOBP_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, GOBP_HEAD_DEVELOPMENT, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_TELENCEPHALON_DEVELOPMENT, chr1q21, GOMF_NOTCH_BINDING, REACTOME_NOTCH2_ACTIVATION_AND_TRANSMISSION_OF_SIGNAL_TO_THE_NUCLEUS, GOBP_NOTCH_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_SIGNALING, REACTOME_EXPRESSION_OF_NOTCH2NL_GENES

GO Biological Process (3): Notch signaling pathway (GO:0007219), cerebral cortex development (GO:0021987), positive regulation of Notch signaling pathway (GO:0045747)

GO Molecular Function (3): Notch binding (GO:0005112), calcium ion binding (GO:0005509), protein binding (GO:0005515)

GO Cellular Component (1): extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by NOTCH2	1
Pre-NOTCH Transcription and Translation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell surface receptor signaling pathway	1
pallium development	1
anatomical structure development	1
Notch signaling pathway	1
regulation of Notch signaling pathway	1
positive regulation of signal transduction	1
signaling receptor binding	1
metal ion binding	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1012 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NOTCH2NLB	ARHGAP11B	Q3KRB8	669
NOTCH2NLB	NBPF11	Q86T75	571
NOTCH2NLB	NBPF10	Q6P3W6	543
NOTCH2NLB	NBPF15	Q8N660	540
NOTCH2NLB	SRGAP2C	P0DJJ0	516
NOTCH2NLB	NBPF19	A0A087WUL8	507
NOTCH2NLB	NBPF20	P0DPF2	507
NOTCH2NLB	NBPF12	Q5TAG4	480
NOTCH2NLB	A0A087WTG0	A0A087WTG0	478
NOTCH2NLB	TMEM14B	Q9NUH8	474
NOTCH2NLB	SRGAP2	O75044	447
NOTCH2NLB	NBPF9	P0DPF3	445
NOTCH2NLB	NBPF4	Q96M43	443
NOTCH2NLB	SRGAP3	O43295	432
NOTCH2NLB	ELANE	P08246	431

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A096LNW5, B8JI71, D3ZHH1, G3I6Z6, O00548, O35516, O57409, P0DPK3, P0DPK4, P35442, P46531, P78504, P97677, Q01705, Q04721, Q05793, Q07008, Q08E66, Q2QI47, Q5G872, Q5ZQU0, Q61483, Q63722, Q66PY1, Q6DI48, Q6NZL8, Q70E20, Q7TQN3, Q7Z3S9, Q8IWY4, Q8IX30, Q8JZM4, Q8K3K1, Q8NFT8, Q8TER0, Q8TEU8, Q8UWJ4, Q8VHS2, Q90Y54, Q90Y57

Diamond homologs: A0A096LNW5, A2RUV0, B4DH59, B8JI71, G3I6Z6, O35516, O75882, P07207, P0DPK3, P0DPK4, P10040, P21783, P46530, P46531, P98160, Q01705, Q04721, Q04756, Q07008, Q20911, Q7Z3S9, Q99466, Q99J86, Q9QW30, Q9UM47, Q9WU60, O35474, O75095, O89019, P13508, P20749, P31695, P82279, Q499M5, Q502K3, Q5RBP1, Q61982, Q6UXI9, Q6UY11, Q810B6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1637 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS111999361 (1:148708824 T>A), RS112316907 (1:148707791 A>G), RS112377837 (1:148710513 G>C), RS112404075 (1:148710641 C>T), RS112453597 (1:148706511 A>T), RS112544926 (1:148620732 C>CA), RS112552732 (1:148707290 A>C,G), RS112659564 (1:148709406 T>C), RS112731245 (1:148709421 C>A,T), RS112976499 (1:148713599 A>C), RS113782795 (1:148711520 T>C), RS113801709 (1:148711521 G>A), RS11487258 (1:148709035 C>T), RS11487276 (1:148706111 A>C,G,T), RS11487682 (1:148710814 T>C)

Disease associations

OMIM: gene MIM:618024 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

2 total (human), top 2 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
abrine	increases expression	1
Lactic Acid	increases expression	1

Clinical trials (associated diseases)

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