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. 2018 Jun 27;8:229. doi: 10.3389/fonc.2018.00229

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Copyright © 2018 Rosati, Baldoni, De Falco, Del Papa, Dorillo, Rompietti, Albi, Falzetti, Di Ianni and Sportoletti.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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NOTCH1 protein structure and signaling activation. (A) The mature NOTCH1 receptor is a heterodimer composed of an extracellular subunit (NOTCH1-EC) and a transmembrane and intracellular subunit (NOTCH1-TMIC). The NOTCH1-EC includes epidermal growth factor (EGF)-like repeats, involved in ligand binding, three LIN-12/NOTCH repeats (LNR), which prevent receptor activation in the absence of ligands, and the heterodimerization domain (HD) involved in non-covalent interactions between the NOTCH1-EC and NOTCH1-TMIC. The NOTCH1-TMIC consists of the transmembrane domain (TM) and the intracellular domain (ICD) (NOTCH1-ICD). NOTCH1-ICD comprises an RBPJ-associated molecule (RAM) domain, seven ankyrin (ANK) repeats, nuclear localization signals (NLS), a transactivation domain (TAD), and a PEST domain, which is involved in proteasomal degradation of active NOTCH1-ICD. (B) Newly synthesized NOTCH1 precursor is cleaved by a furin-like convertase (Furin) in the Golgi apparatus to generate the mature receptor. NOTCH1 signaling initiates when a JAGGED or DELTA ligand expressed on a signal sending cell interacts with NOTCH1 on a signal receiving cell. This interaction triggers two sequential cleavages of NOTCH1: the first, by an a disintegrin and metalloproteinase (ADAM) metalloproteinase, generates the substrate for the second cleavage by γ-secretase, which releases the active NOTCH1-ICD. NOTCH1-ICD translocates to the nucleus where it forms a transcriptional activation complex by interacting with the transcription factor CSL/RBP-Jk, mastermind-like proteins, and others coactivators (CoA), leading to the expression of NOTCH1 target genes. In physiological conditions, NOTCH1 signal attenuation is mediated by ubiquitination and proteasomal degradation of NOTCH1-ICD.