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notch-1 (Drosophila) homolog protein; translocation-associated notch homolog (NOTCH1, TAN1)

Function: - receptor for membrane-bound ligands Jagged1, Jagged2 & delta1 to regulate cell-fate determination - affects implementation of differentiation, proliferation & apoptosis - role in normal lymphocyte function (putative) - role in maturation of both CD4+ & CD8+ cells in the thymus - role in follicular differentiation & cell fate selection within the follicle (putative) - contact-mediated Notch1 signaling regulates capacity of neurons to extend & elaborate neurites - formation of neuronal contacts results in activation of Notch receptors, leading to restriction of neuronal growth & a subsequent arrest in maturity - during cerebellar development, may function as a receptor for neuronal DNER & may be involved in the differentiation of Bergmann glia - Notch1 activation promotes the survival of neural & pancreatic stem cells. [4] - Notch1 activation induces the expression of the specific target genes hairy & enhancer of split (Hes3, HEYL) & Sonic hedgehog (Shh) through activation of Akt, STAT3 & mammalian target of rapamycin - there is proteolytic processing in maturation & activation of NOTCH1 - maturation of NOTCH1 is mediated by a furin-like convertase within the secretory pathway; cleavage occurs at an extracellular site (S1); the resultant polypeptides associate as an intramolecular heterodimer thought to be the only form of NOTCH1 on the cell surface - ligand binding facilitates ADAM17 (alpha-secretase)-mediated cleavage within the extracellular juxtamembrane region between Ala1710 & Val1711 (S2) to generate a transient intermediate peptide 'NEXT' (Notch extracellular truncation) [2] - NEXT is a substrate of presenilin-dependent gamma-secretase - NEXT cleavage occurs between Gly1743 & Val1744 of parent Notch1 (S3); cleavage releases the NOTCH1 intracellular domain (NICD) from the membrane; NICD then translocates to the nucleus, where it functions as a transcriptional activator in concert with CSL proteins - NICD forms a transcriptional activator complex with RBP-J kappa & activates genes of the enhancer of split locus - interacts with DNER, DTX1, DTX2 & RBPSUH - also interacts with MAML1, MAML2 & MAML3 which act as transcriptional coactivators for NOTCH1 - phosphorylated (putative) - regulators of Notch1: a) NOTCH1 is negatively regulated by SPEN b) DTX4 Structure: - belongs to the NOTCH family - contains 5 ANK repeats - contains 36 EGF-like domains - contains 3 LNR (lin/notch) repeats Compartment: - cell membrane - notch 1 intracellular domain (NICD): nucleus; following proteolytical processing NICD is translocated to the nucleus (putative) Expression: - in fetal tissues most abundant in spleen, brain stem & lung. - also present in most adult tissues where it is found mainly in lymphoid tissues Pathology: - chromosomal translocation t(7;9)(q34;q34.3) resulting in truncation of Notch-1 transcripts have been identified in 3 cases of acute T-cell lymphoblastic leukemia - in altered form, may contribute to transformation or progression in some T-cell neoplasms - defects in NOTCH1 are a cause of aortic valvular stenosis; an early developmental defect in the aortic valve & a later de-repression of Ca+2 deposition with progressive aortic valve calcification

Interactions

molecular events

Related

furin (Paired Basic Amino acid residue-Cleaving Enzyme {PACE}, kexin homolog, paired-basic endopeptidase, prohormone-processing endoprotease, serine proteinase homolog fur) Notch1 proto-oncogene presenilin

General

ankyrin repeat domain protein (ANKRD) Ca+2 binding protein glycoprotein notch (Drosophila) homolog protein

Properties

SIZE: MW = 261 kD entity length = 2444 aa COMPARTMENT: plasma membrane MOTIF: signal sequence {1-18} EGF domain {20-1426} (36) calcium-binding EGF-like domain (18) Notch/Lin12 repeat (3) N-glycosylation site {N1587} arginine-rich region {1661-1664} MOTIF: arginine residue (SEVERAL) proteolytic site {1664-1665} proline-rich region SITE: 1728-1731 MOTIF: proline residue (SEVERAL) transmembrane domain glutamate-rich region {1901-1904} MOTIF: glutamate residue (SEVERAL) ankyrin repeat NAME: ankyrin repeat (6) glutamine-rich region {2403-2406} MOTIF: glutamine residue (SEVERAL) proline-rich region SITE: 2410-2417 MOTIF: proline residue (SEVERAL) serine-rich region {2521-2524} MOTIF: serine residue (SEVERAL)

Database Correlations

OMIM correlations MORBIDMAP 190198 UniProt P46531 PFAM correlations Entrez Gene 4851 Kegg hsa:4851

References

  1. OMIM :accession 190198
  2. De Strooper B, Annaert W. Where Notch and Wnt signaling meet. The presenilin hub. J Cell Biol. 2001 Feb 19;152(4):F17-20. No abstract available. PMID: 11266476
  3. Entrez Gene :accession 4851
  4. Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae SK, Kittappa R, McKay RD. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature. 2006 Aug 17;442(7104):823-6. Epub 2006 Jun 25. PMID: 16799564
  5. UniProt :accession P46531
  6. Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/NOTCH1ID30ch9q34.html