Pathway Human Homo sapiens

Signaling by NOTCH3

R-HSA-9012852 in Reactome release 97: under Signaling by NOTCH, with 49 genes placed in it by the mapping files and 2 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-9012852 (mouse), R-RNO-9012852 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-9012852.3
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2005-06-12
Events inside: 2, counted from the record

Similar to NOTCH1, NOTCH3 is activated by delta-like and jagged ligands (DLL/JAG) expressed in trans on a neighboring cell. The activation triggers cleavage of NOTCH3, first by ADAM10 at the S2 cleavage site, then by gamma-secretase at the S3 cleavage site, resulting in the release of the intracellular domain of NOTCH3, NICD3, into the cytosol. NICD3 subsequently traffics to the nucleus where it acts as a transcriptional regulator. NOTCH3 expression pattern is more restricted than the expression patterns of NOTCH1 and NOTCH2, with predominant expression of NOTCH3 in vascular smooth muscle cells, lymphocytes and the nervous system (reviewed by Bellavia et al. 2008). Based on the study of Notch3 knockout mice, Notch3 is not essential for embryonic development or fertility (Krebs et al. 2003).

Germline gain-of-function NOTCH3 mutations are an underlying cause of the CADASIL syndrome - cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CADASIL is characterized by degeneration and loss of vascular smooth muscle cells from the arterial wall, predisposing affected individuals to an early onset stroke (Storkebaum et al. 2011). NOTCH3 promotes survival of vascular smooth muscle cells at least in part by induction of CFLAR (c FLIP), an inhibitor of FASLG activated death receptor signaling. The mechanism of NOTCH3 mediated upregulation of CFLAR is unknown; it is independent of the NOTCH3 coactivator complex and involves an unelucidated crosstalk with the RAS/RAF/MAPK pathway (Wang et al. 2002).

In rat brain, NOTCH3 and NOTCH1 are expressed at sites of adult neurogenesis, such as the dentate gyrus (Irvin et al. 2001). NOTCH3, similar to NOTCH1, promotes differentiation of the rat adult hippocampus derived multipotent neuronal progenitors into astroglia (Tanigaki et al. 2001). NOTCH1, NOTCH2, NOTCH3, and their ligand DLL1 are expressed in neuroepithelial precursor cells in the neural tube of mouse embryos. Together, they signal to inhibit neuronal differentiation of neuroepithelial precursors. Expression of NOTCH3 in mouse neuroepithelial precursors is stimulated by growth factors BMP2, FGF2, Xenopus TGF beta5 - homologous to TGFB1, LIF, and NTF3 (Faux et al. 2001).

In mouse telencephalon, NOTCH3, similar to NOTCH1, promotes radial glia and neuronal progenitor phenotype. This can, at least in part be attributed to NOTCH mediated activation of RBPJ-dependent and HES5-dependent transcription (Dang et al. 2006).

In mouse spinal cord, Notch3 is involved in neuronal differentiation and maturation. Notch3 knockout mice have a decreased number of mature inhibitory interneurons in the spinal cord, which may be involved in chronic pain conditions (Rusanescu and Mao 2014).

NOTCH3 amplification was reported in breast cancer, where NOTCH3 promotes proliferation and survival of ERBB2 negative breast cancer cells (Yamaguchi et al. 2008), and it has also been reported in ovarian cancer (Park et al. 2006). NOTCH3 signaling is involved in TGF beta (TGFB1) signaling-induced eptihelial to mesenchimal transition (EMT) (Ohashi et al. 2011, Liu et al. 2014)

NOTCH3 indirectly promotes development of regulatory T cells (Tregs). NOTCH3 signaling activates pre-TCR-dependent and PKC-theta (PRKCQ)-dependent NF-kappaB (NFKB) activation, resulting in induction of FOXP3 expression (Barbarulo et al. 2011). Deregulated NOTCH3 and pre-TCR signaling contributes to development of leukemia and lymphoma (Bellavia et al. 2000, Bellavia et al. 2002).

Literature Reactome attaches

Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fateNeuron, 2001, vol. 29, p. 45-55PubMed 11182080
Expression patterns of Notch1, Notch2, and Notch3 suggest multiple functional roles for the Notch-DSL signaling system during brain developmentJ. Comp. Neurol., 2001, vol. 436, p. 167-81PubMed 11438922
Interactions between fibroblast growth factors and Notch regulate neuronal differentiationJ. Neurosci., 2001, vol. 21, p. 5587-96PubMed 11466430
Notch3 signaling in vascular smooth muscle cells induces c-FLIP expression via ERK/MAPK activation. Resistance to Fas ligand-induced apoptosisJ. Biol. Chem., 2002, vol. 277, p. 21723-9PubMed 11925448
Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutationGenesis, 2003, vol. 37, p. 139-43PubMed 14595837
Notch3 signaling promotes radial glial/progenitor character in the mammalian telencephalonDev. Neurosci., 2006, vol. 28, p. 58-69PubMed 16508304

Reactome's record lists 4 orthologous events, R-RNO-9012852 (Rattus norvegicus), R-MMU-9012852 (Mus musculus) among the species this site serves, and 2 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-09-30 ET · Reactome pathway browser"Signaling by NOTCH3". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-9012852 with StableID: R-HSA-9012852.3 (accessed 2026-09-30 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 49 genes in this human pathway; showing 1 to 49, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneADAM10	AuthorityHGNC:188	Mapping file id102 NCBI file	EvidenceTAS
GeneAPH1A	AuthorityHGNC:29509	Mapping file id51107 NCBI file	EvidenceTAS
GeneAPH1B	AuthorityHGNC:24080	Mapping file id83464 NCBI file	EvidenceTAS
GeneCREBBP	AuthorityHGNC:2348	Mapping file id1387 NCBI file	EvidenceIEA, TAS
GeneDLGAP5	AuthorityHGNC:16864	Mapping file id9787 NCBI file	EvidenceTAS
GeneDLL1	AuthorityHGNC:2908	Mapping file id28514 NCBI file	EvidenceIEA, TAS
GeneDLL4	AuthorityHGNC:2910	Mapping file id54567 NCBI file	EvidenceIEA, TAS
GeneEGF	AuthorityHGNC:3229	Mapping file id1950 NCBI file	EvidenceTAS
GeneEGFR	AuthorityHGNC:3236	Mapping file id1956 NCBI file	EvidenceTAS
GeneEP300	AuthorityHGNC:3373	Mapping file id2033 NCBI file	EvidenceIEA, TAS
GeneFABP7	AuthorityHGNC:3562	Mapping file id2173 NCBI file	EvidenceIEA
GeneHES1	AuthorityHGNC:5192	Mapping file id3280 NCBI file	EvidenceIEA
GeneHES5	AuthorityHGNC:19764	Mapping file id388585 NCBI file	EvidenceIEA
GeneHEY1	AuthorityHGNC:4880	Mapping file id23462 NCBI file	EvidenceIEA
GeneHEY2	AuthorityHGNC:4881	Mapping file id23493 NCBI file	EvidenceIEA
GeneHEYL	AuthorityHGNC:4882	Mapping file id26508 NCBI file	EvidenceTAS
GeneIKZF1	AuthorityHGNC:13176	Mapping file id10320 NCBI file	EvidenceIEA
GeneJAG1	AuthorityHGNC:6188	Mapping file id182 NCBI file	EvidenceIEA, TAS
GeneJAG2	AuthorityHGNC:6189	Mapping file id3714 NCBI file	EvidenceIEA, TAS
GeneKAT2A	AuthorityHGNC:4201	Mapping file id2648 NCBI file	EvidenceIEA, TAS
GeneKAT2B	AuthorityHGNC:8638	Mapping file id8850 NCBI file	EvidenceIEA, TAS
GeneMAML1	AuthorityHGNC:13632	Mapping file id9794 NCBI file	EvidenceIEA, TAS
GeneMAML2	AuthorityHGNC:16259	Mapping file id84441 NCBI file	EvidenceIEA, TAS
GeneMAML3	AuthorityHGNC:16272	Mapping file id55534 NCBI file	EvidenceIEA, TAS
GeneMAMLD1	AuthorityHGNC:2568	Mapping file id10046 NCBI file	EvidenceIEA, TAS
GeneMIB1	AuthorityHGNC:21086	Mapping file id57534 NCBI file	EvidenceIEA
GeneMIB2	AuthorityHGNC:30577	Mapping file id142678 NCBI file	EvidenceIEA
GeneNCSTN	AuthorityHGNC:17091	Mapping file id23385 NCBI file	EvidenceTAS
GeneNEURL1	AuthorityHGNC:7761	Mapping file id9148 NCBI file	EvidenceIEA
GeneNEURL1B	AuthorityHGNC:35422	Mapping file id54492 NCBI file	EvidenceIEA
GeneNOTCH1	AuthorityHGNC:7881	Mapping file id4851 NCBI file	EvidenceIEA, TAS
GeneNOTCH3	AuthorityHGNC:7883	Mapping file id4854 NCBI file	EvidenceIEA, TAS
GenePBX1	AuthorityHGNC:8632	Mapping file id5087 NCBI file	EvidenceTAS
GenePLXND1	AuthorityHGNC:9107	Mapping file id23129 NCBI file	EvidenceTAS
GenePSEN1	AuthorityHGNC:9508	Mapping file id5663 NCBI file	EvidenceTAS
GenePSEN2	AuthorityHGNC:9509	Mapping file id5664 NCBI file	EvidenceTAS
GenePSENEN	AuthorityHGNC:30100	Mapping file id55851 NCBI file	EvidenceTAS
GenePTCRA	AuthorityHGNC:21290	Mapping file id171558 NCBI file	EvidenceIEA
GeneRBPJ	AuthorityHGNC:5724	Mapping file id3516 NCBI file	EvidenceIEA, TAS
GeneRPS27A	AuthorityHGNC:10417	Mapping file id6233 NCBI file	EvidenceIEA, TAS
GeneSNW1	AuthorityHGNC:16696	Mapping file id22938 NCBI file	EvidenceIEA, TAS
GeneSTAT1	AuthorityHGNC:11362	Mapping file id6772 NCBI file	EvidenceIEA, TAS
GeneTACC3	AuthorityHGNC:11524	Mapping file id10460 NCBI file	EvidenceIEA
GeneUBA52	AuthorityHGNC:12458	Mapping file id7311 NCBI file	EvidenceIEA, TAS
GeneUBB	AuthorityHGNC:12463	Mapping file id7314 NCBI file	EvidenceIEA, TAS
GeneUBC	AuthorityHGNC:12468	Mapping file id7316 NCBI file	EvidenceIEA, TAS
GeneWWC1	AuthorityHGNC:29435	Mapping file id23286 NCBI file	EvidenceTAS
GeneWWP2	AuthorityHGNC:16804	Mapping file id11060 NCBI file	EvidenceTAS
GeneYBX1	AuthorityHGNC:8014	Mapping file id4904 NCBI file	EvidenceTAS

Evidence codes on this page: IEA, TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

Signaling by NOTCHR-HSA-157118241 genes

Children

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.