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Details on Person UniProt:Q04721 NOTCH2
| Class:Id | ReferenceGeneProduct:60522 |
|---|---|
| _chainChangeLog | signal peptide:1-25 added on Sat February 7 2015;chain:26-2471 added on Sat February 7 2015;chain:1666-2471 added on Sat February 7 2015;chain:1697-2471 added on Sat February 7 2015 |
| _displayName | UniProt:Q04721 NOTCH2 |
| _timestamp | 2026-02-20 23:08:25 |
| chain | signal peptide:1-25 chain:26-2471 chain:1666-2471 chain:1697-2471 |
| checksum | 605B1B963C812BE1 |
| comment | FUNCTION Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus (PubMed:21378985, PubMed:21378989). Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). Involved in bone remodeling and homeostasis. In collaboration with RELA/p65 enhances NFATc1 promoter activity and positively regulates RANKL-induced osteoclast differentiation (PubMed:29149593). Positively regulates self-renewal of liver cancer cells (PubMed:25985737).SUBUNIT Heterodimer of a C-terminal fragment N(TM) and an N-terminal fragment N(EC) which are probably linked by disulfide bonds (By similarity). Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH2. Interacts with RELA/p65 (By similarity). Interacts with HIF1AN. Interacts (via ANK repeats) with TCIM, the interaction inhibits the nuclear translocation of NOTCH2 N2ICD (PubMed:25985737). Interacts with CUL1, RBX1, SKP1 and FBXW7 that are SCF(FBXW7) E3 ubiquitin-protein ligase complex components (PubMed:29149593). Interacts with MINAR1; this interaction increases MINAR1 stability and function (PubMed:29329397). Interacts with NOTCH2NL (NOTCH2NLA, NOTCH2NLB and/or NOTCH2NLC); leading to enhance Notch signaling pathway in a non-cell-autonomous manner (PubMed:29856954). Interacts with MDK; this interaction mediates a nuclear accumulation of NOTCH2 and therefore activation of NOTCH2 signaling leading to interaction between HES1 and STAT3 (PubMed:18469519). Interacts with MINAR2 (PubMed:32954300).INTERACTION Following proteolytical processing NICD is translocated to the nucleus. Retained at the cytoplasm by TCIM (PubMed:25985737).TISSUE SPECIFICITY Expressed in the brain, heart, kidney, lung, skeletal muscle and liver. Ubiquitously expressed in the embryo.PTM Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form (By similarity). Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC) (By similarity). Following ligand binding, it is cleaved by TNF converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT) (By similarity). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane (By similarity).PTM Hydroxylated by HIF1AN.PTM Can be either O-glucosylated or O-xylosylated at Ser-613 by POGLUT1.PTM Phosphorylated by GSK3. GSK3-mediated phosphorylation is necessary for NOTCH2 recognition by FBXW7, ubiquitination and degradation via the ubiquitin proteasome pathway.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry. NOTCH2 nonsense and frameshift mutations associated with Hajdu-Cheney syndrome cluster to the last coding exon of the gene. Mutant mRNA products escape nonsense-mediated decay and the resulting truncated NOTCH2 proteins act in a gain-of-function manner (PubMed:21378989). The pathological mechanism at cellular level involves disruption of a high affinity degron recognized by FBXW7 at the C-terminus, loss of interaction with FBXW7, reduced ubiquitination and degradation, and increased NOTCH2 levels. Bone marrow cells derived from HJCYS patients have an enhanced capacity of osteoclastogenesis due to sustained NOTCH2 activity (PubMed:29149593).SIMILARITY Belongs to the NOTCH family. |
| description | recommendedName: fullName evidence="28"Neurogenic locus notch homolog protein 2 shortName: Notch 2 shortName: hN2 component recommendedName: Notch 2 extracellular truncation shortName evidence="27"N2ECD /component component recommendedName: Notch 2 intracellular domain shortName evidence="27"N2ICD /component |
| geneName | NOTCH2 |
| identifier | Q04721 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Activator ANK repeat Cell membrane Cytoplasm Developmental protein Differentiation Disease variant Disulfide bond EGF-like domain Glycoprotein Membrane Notch signaling pathway Nucleus Osteoporosis Phosphoprotein Proteomics identification Receptor Reference proteome Repeat Signal Transcription Transcription regulation Transmembrane Transmembrane helix Ubl conjugation |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20 |
| name | NOTCH2 |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:1606762] ENSEMBL:ENSG00000134250 NOTCH2 [Homo sapiens] |
| secondaryIdentifier | NOTC2_HUMAN Q5T3X7 Q99734 Q9H240 |
| sequenceLength | 2471 |
| species | [Species:48887] Homo sapiens |
| (referenceEntity) | [EntityWithAccessionedSequence:156987] NOTCH2(26-1581) [Golgi lumen] [Homo sapiens] [EntityWithAccessionedSequence:157010] NOTCH2(26-2471) [Golgi lumen] [Homo sapiens] [EntityWithAccessionedSequence:157017] NOTCH2(1582-2471) [Golgi membrane] [Homo sapiens] [EntityWithAccessionedSequence:157025] Pre-NOTCH2 [endoplasmic reticulum membrane] [Homo sapiens] [EntityWithAccessionedSequence:157202] NOTCH2(26-1581) [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:157225] NEXT2 [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:157228] NOTCH2(1582-2471) [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:157628] NOTCH2(1666-1696) [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:157642] NICD2 [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:157652] NOTCH2(1582-1665) [extracellular region] [Homo sapiens] |
| (referenceSequence) | [ModifiedResidue:1467295] O-fucosyl-L-threonine at 1039 [ModifiedResidue:1467300] O-fucosyl-L-threonine at 771 [ModifiedResidue:1467301] O-fucosyl-L-serine at 925 [ModifiedResidue:1467310] O-fucosyl-L-threonine at 470 [ModifiedResidue:1467318] O-glucosyl-L-serine at 462 [ModifiedResidue:1467319] O-glucosyl-L-serine at 1031 [ModifiedResidue:1467321] O-glucosyl-L-serine at 879 [ModifiedResidue:1467323] O-glucosyl-L-serine at 1155 [ModifiedResidue:1467327] O-fucosyl-L-threonine at 120 [ModifiedResidue:1467328] O-fucosyl-L-threonine at 809 |
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No pathways have been reviewed or authored by UniProt:Q04721 NOTCH2 (60522)
