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.
• 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)
• 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:
  • NOTCH1 is negatively regulated by SPEN
  • 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

More general terms

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

Additional terms

• 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

Database

• UniProt: http://www.uniprot.org/uniprot/P46531.html
• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4851
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:4851
• OMIM: https://mirror.omim.org/entry/109730
• OMIM: https://mirror.omim.org/entry/190198