Notch-1

Notch-1, also known as Notch homolog 1, is a member of the Notch family. This type-1 transmembrane protein includes an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of different domain types. Notch-1 plays an important role in T cell lineage induction. Notch-1 deficiency in skin and in primary keratinocytes results in increased and sustained expression of Gli2, causing the development of basal-cell carcinoma-like tumors. Furthermore, Notch1 inactivation in the epidermis results in derepressed beta-catenin signaling in cells that should normally undergo differentiation. Enhanced beta-catenin signaling can be reversed by re-introduction of a dominant active form of the Notch-1 receptor. This leads to a reduction in the signaling-competent pool of beta-catenin, indicating that Notch-1 can inhibit beta-catenin-mediated signaling. Results indicate that Notch1 functions as a tumor-suppressor protein in mammalian skin.

Notch-1 Related Areas

Signal Transduction>>Notch Signaling Pathway>> Notch1

Stem Cell>>Notch Signaling Pathway>> Notch1

Cancer>>Cancer Stem Cell (CSC)>> Notch1

Notch-1 Alternative Names

RP23-306D20.12-001, 9930111A19Rik, Mis6, Tan1, lin-12, Motch A; mT14; major type A protein; neurogenic locus notch homolog protein 1 [Mus musculus]

Summaries for Notch-1

Entrez Gene summary for Notch1:

This Notch1 gene encodes a member of the Notch family. Members of this Type 1 transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway which regulates interactions between physically adjacent cells. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signaling pathway that plays a key role in development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remain to be determined. Notch-1 is cleaved in the trans-Golgi network, and presented on the cell surface as a heterodimer. Notch-1 functions as a receptor for membrane bound ligands, and may play multiple roles during development. [provided by RefSeq, Jul 2008]

OMIM - description for Notch-1:

Notch proteins are single-pass transmembrane receptors that regulate cell fate decisions during development. The Notch family includes 4 receptors, NOTCH1, NOTCH2 (600275), NOTCH3 (600276), and NOTCH4 (164951), whose ligands include JAG1 (601920), JAG2 (602570), DLL1 (606582), DLL3 (602768), and DLL4 (605185). All of the receptors have an extracellular domain containing multiple epidermal growth factor (EGF; 131530)-like repeats and an intracellular region containing the RAM domain, ankyrin repeats, and a C-terminal PEST domain (Das et al., 2004).

Wikipedia summary for Notch-1:

Notch homolog 1, translocation-associated (Drosophila), also known as Notch-1, is a human gene encoding a single-pass transmembrane receptor.
A deficiency can be associated with bicuspid aortic valve. There is evidence that activated Notch-1 and Notch 3 promote differentiation of progenitor cells into astroglia. Interestingly, Notch-1, then activated before birth, induces radial glia differentiation, but postnatally induces the differentiation into astrocytes. One study shows that Notch-1 cascade is activated by Reelin in an unidentified way. Reelin and Notch1 cooperate in the development of the dentate gyrus, according to another.

Human Notch-1 Protein General Information

 

• Protein names: Neurogenic locus notch homolog protein 1, Short name=Notch 1
• Sequence length: 2555 AA.
• Sequence similarities: Notch-1 belongs to the NOTCH family. Notch-1 contains 5 ANK repeats. Notch-1 contains 36 EGF-like domains. Notch-1 contains 3 LNR (Lin/Notch) repeats.
• Post-translational modification: 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. Phosphorylated
• Subunit structure: Heterodimer of a C-terminal fragment N(TM) and an N-terminal fragment N(EC) which are probably linked by disulfide bonds. Notch-1 interacts with DNER, DTX1, DTX2 and RBPJ/RBPSUH. Notch-1 also interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH1. The activated membrane-bound form interacts with AAK1 which promotes NOTCH1 stabilization. Forms a trimeric complex with FBXW7 and SGK1. Notch-1 interacts with HIF1AN. HIF1AN negatively regulates the function of notch intracellular domain (NICD), accelerating myogenic differentiation
• Subcellular location: Cell membrane; Single-pass type I membrane protein.
  Notch-1 intracellular domain: Nucleus By similarity. Note: Following proteolytical processing NICD is translocated to the nucleus
• Tissue specificity: In fetal tissues most abundant in spleen, brain stem and lung. Also present in most adult tissues where it is found mainly in lymphoid tissues.
• Involvement in disease: Defects in Notch-1 are a cause of bicuspid aortic valve (BAV) [MIM:109730]. A common defect in the aortic valve in which two rather than three leaflets are present. It is often associated with aortic valve calcification and insufficiency. In extreme cases, the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome.

General information above from UniProt

Function for Notch-1 Protein

UniProtKB:

Notch-1 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. Notch-1 affects the implementation of differentiation, proliferation and apoptotic programs. Notch-1 may be important for normal lymphocyte function. In altered form, may contribute to transformation or progression in some T-cell neoplasms. Notch-1 is involved in the maturation of both CD4+ and CD8+ cells in the thymus. Notch-1 may be important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, Notch-1 may function as a receptor for neuronal DNER and may be involved in the differentiation of Bergmann glia. Notch-1 represses neuronal and myogenic differentiation. Notch-1 may enhance HIF1A function by sequestering HIF1AN away from HIF1A.

Genatlas:

• Notch-1 functions as a receptor for membrane bound ligands and plays a role in a variety of developmental processes by controlling cell fate decisions during hematopoiesis
• Notch signals regulate development and differentiation of adult self-renewing cells
• Notch-1 is receptor for membrane-bound ligands Jagged1, Jagged2, Delta-like1, Delta-like3 and Delta-like4
• Notch-1 controlls binary cell fate decisions during developement
• Notch-1 induces delay of hematopoietic differentiation and alteration of cell cycle kinetics
• Notch-1 mediates cell-cell interactions that specify cell fate during development, and the changes of the endometrium during menstrual cycle and development of endometrial cancers
• Notch-1 regulates T-cell development
• Notch-1 playing a fundamental role during the establishment of cell fates in the central nervous system (CNS) by regulating neural cell differentiation
• Notch-1 provides a CNTF-independent instructive signal of astroglia differentiation in central nervous system multipotent progenitor cells
• Notch-1 plays a role in early embryonic development like the establishment of the rostro-caudal polarity of somites
• Notch-1 plays a role in neuronal development by regulating the capacity of neurons to extend and elaborate neurites
• Notch-1 is involved in human keratinocyte tumor suppression
• Notch-1 signaling pathway is a critical controller of cell fate decisions and is a key regulator of cell growth and metabolism during T-cell development and transformation
• Notch-1 pathway is crucial in podocyte development
• Notch-1 acts as a net inhibitor of bone resorption, exerting its effect both directly in osteoclast precursors and indirectly via osteoblast lineage cells
• Notch signaling is involved in endothelial–mesenchymal transformation in the ventricular chamber, atrioventricular valves and vasculature
• Notch-1 may have critical implications in the control of heart homeostasis and its adaptation to pathologic states
• with RELN necessary to induce the expression of brain lipid binding protein (FABP7) and to promote the process extension and the maturation of the neuronal progenitors, the radial glial cells
• Notch-1acts in aged muscle regeneration and bone homeostasis by regulating both osteoclastogenesis and osteoblastic proliferation and by maintaining a pool of mesenchymal progenitors in bone mrarrow
• Notch-1 functions as a tumor suppressor gene in mammalian skin
• as other Notch family members and ligands, expressed in the human corneal epithelium and appear to play pivotal roles in corneal epithelial cell differentiation
• new signaling pathway involved in holoprosencephaly
• Notch-1 signalling is necessary for the initial phases of myogenesis of dorsomedial lip cells
• role for Notch signalling during early haematopoietic stem cell differentiation, suggesting that the Notch pathway can play both tumour-promoting and -suppressive roles within the same tissue
• Notch-1 may function as a tumor suppressor gene rather than an oncogene in Head and neck squamous cell carcinoma

Homology for human Notch-1

• ortholog to LOC493574, Rattus norvegicus
• ortholog to NOTCH1, pan troglodytes
• ortholog to Notch1, Mus musculus
• ortholog to zgc:154151, Danio rerio

Phenotype Information for Notch-1

• Gene/Locus: SEC16A, SEC16L, KIAA0310, p250
• Phenotype: Aortic valve disease
  Leukemia, T-cell acute lymphoblastic

Phenotype Information for Notch-1 from OMIM (Online Mendelian Inheritance in Man)