Notch signaling (Homo sapiens)

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The Notch pathway is an evolutionally conserved signalling pathway which plays an important role in diverse developmental and physiological processes. These include cell-fate determination, tissue patterning and morphogenesis, cell differentiation, proliferation and cell death. The Notch pathway is named after the Drosophila mutants that showed irregular notches of missing tissue at the insect wing blade tips. The Notch gene was cloned in 1985. Proteins of the Notch families are single-pass transmembrane proteins that function both as cell surface receptors and nuclear transcriptional regulators. Four Notch receptors (Notch 1-4) have been identified in mammals. Mature Notch receptors are non-covalent heterodimers consisting of an extracellular subunit (NEC) and a transmembrane subunit (NTM). NEC possess multiple EGF-like repeats and three specialized Lin-Notch repeats (LNR) that forms a tight hydrophobic interaction with extracellular stump of NTM. This region masks an ‘A disintegrin and metalloprotease’ (ADAM) cleavage site. The region where these two subunits interact is called the heterodimerization domain (HD) (4). Notch ligands are also transmembrane proteins with multiple EGF-like repeats, a short cytoplasmic tail and a specialized delta-serrate-lag2 (DSL) domain at the N-terminus. There are five canonical Notch ligands – Jagged (JAG1 and JAG2), Delta-like (DLL1, DLL3, DLL4) in mammals. Notch signalling activation occurs upon ligand-receptor binding, which are expressed on two adjacent cells. Ligand binding causes dissociation of NEC from NTM, unmasking the ADAM cleavage site. The NEC fragment is trans- endocytosed into the ligand expressing cells. The full-length receptor minus the NEC fragment is cleaved at the membrane by ADAM17 generating an intermediate, Notch extracellular truncation (NEXT). This is further cleaved by γ-secretase that generates an active Notch intracellular fragment (NIC) or Notch intracellular domain (NICD). The γ- secretase complex is composed of PSEN1, PSEN2, PSENEN, NCSTN and APH1 (A or B). Following these two cleavage steps, the NICD is released into the cytoplasm and translocates into the nucleus to regulate transcription of Notch target genes. Upon translocation into the nucleus, NICD binds to RBPJ which is a constitutive repressor of Notch signalling. RBPJ represses Notch target gene expression by recruiting a co-repressor complex, which includes NCOR1, NCOR2, SNW1, CIR, HDAC1, HDAC2, SPEN and FHL1 and SAP30. NICD binding to RBPJ replaces the co-repressor complex with a co-activator complex which includes MAML1-3, EP300 and SNW1. Primary Notch target genes include two families of transcriptional factors – Hes, including HES1 and HES5 as well as Hey including HEY1 and HEY2. Other Notch target genes include CCND1, CDKN1A, GATA3 and PTCRA. CNTN1 acts as a functional ligand of Notch. This trans-extracellular interaction causes gamma-secretase-dependent nuclear translocation of the NICD. This signalling is involved in oligodendrocyte precursor cell differentiation and upregulation of myelin-related protein MAG. In addition to the canonical Notch pathway, there is increasing evidence showing RBPJ independent non-canonical pathways. been fully characterized. Physical interaction of NOTCH-1IC with LCK- PI3K may mediate non-nuclear cross-talk with AKT, leading to survival signalling. Notch stimulation through AKT pathway leads to down regulation of MYC expression. Activation of SRC/STAT3 pathway by Notch signaling is dependent on the expression of Notch effector HES1 transcription factor. The induction of HES1 enhanced SRC phosphorylation. This activated SRC kinase was found to be responsible for the enhanced phosphorylation of STAT3. The HES1 and HES5 proteins associate with and facilitate the complex formation between JAK2 and STAT3, thus promoting STAT3 phosphorylation and activation. The activated STAT3 translocates from the cytoplasm to the nucleus and induces transcriptional activation of target gene expression (including HIF1A). NetPath (http://www.netpath.org) is a collaborative effort between PandeyLab at Johns Hopkins University (http://pandeylab.igm.jhmi.edu) and Institute of Bioinformatics (http://www.ibioinformatics.org). This version of the pathway is available at NetSlim (http://www.netpath.org/netslim). If you use this pathway, please cite the NetPath website.