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MGP002118

UniProt Annotations

Entry Information

Gene Name	notch 2
Protein Entry	NOTC2_HUMAN
UniProt ID	Q04721
Species	Human

Comments

Comment type	Description
Disease	Alagille syndrome 2 (ALGS2) [MIM:610205]: A form of Alagille syndrome, an autosomal dominant multisystem disorder. It is clinically defined by hepatic bile duct paucity and cholestasis in association with cardiac, skeletal, and ophthalmologic manifestations. There are characteristic facial features and less frequent clinical involvement of the renal and vascular systems. {ECO:0000269\|PubMed:16773578}. Note=The disease is caused by mutations affecting the gene represented in this entry.
Disease	Hajdu-Cheney syndrome (HJCYS) [MIM:102500]: A rare skeletal disorder characterized by the association of facial anomalies, acro-osteolysis, general osteoporosis, insufficient ossification of the skull, and periodontal disease (premature loss of permanent teeth). Other features include cleft palate, congenital heart defects, polycystic kidneys, orthopedic problems and anomalies of the genitalia, intestines and eyes. {ECO:0000269\|PubMed:21378985, ECO:0000269\|PubMed:21378989}. Note=The disease is caused by mutations affecting the gene represented in this entry. NOTCH2 mutations associated with Hajdu- Cheney syndrome cluster to the last coding exon of the gene. This suggests that the mutant mRNA products may escape nonsense- mediated decay and the resulting truncated NOTCH2 proteins act in a gain-of-function manner.
Function	Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 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. 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. {ECO:0000250, ECO:0000269\|PubMed:21378985, ECO:0000269\|PubMed:21378989}.
Ptm	Can be either O-glucosylated or O-xylosylated at Ser-613 by POGLUT1. {ECO:0000250}.
Ptm	Hydroxylated by HIF1AN. {ECO:0000269\|PubMed:18299578}.
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. Cleavage results in a C- terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). 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). {ECO:0000250}.
Similarity	Belongs to the NOTCH family. {ECO:0000305}.
Similarity	Contains 35 EGF-like domains. {ECO:0000255\|PROSITE- ProRule:PRU00076}.
Similarity	Contains 3 LNR (Lin/Notch) repeats. {ECO:0000255\|PROSITE-ProRule:PRU00525}.
Similarity	Contains 6 ANK repeats. {ECO:0000255\|PROSITE- ProRule:PRU00023}.
Subcellular Location	Cell membrane; Single-pass type I membrane protein.
Subcellular Location	Notch 2 intracellular domain: Nucleus. Note=Following proteolytical processing NICD is translocated to the nucleus.
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. {ECO:0000250, ECO:0000269\|PubMed:11101851, ECO:0000269\|PubMed:12370315, ECO:0000269\|PubMed:17573339}.
Tissue Specificity	Expressed in the brain, heart, kidney, lung, skeletal muscle and liver. Ubiquitously expressed in the embryo. {ECO:0000269\|PubMed:21378985}.
Web Resource	Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/NOTCH2ID41556ch1p12.html";