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Fig. 1 | Journal of Biomedical Science

Fig. 1

From: Notch-ing up knowledge on molecular mechanisms of skin fibrosis: focus on the multifaceted Notch signalling pathway

Fig. 1

An overview of Notch maturation, activation and processing. Before integration into the plasma membrane, Notch receptor is decorated with different glycans by a complex series of enzymatic reactions occurring within the endoplasmic reticulum (ER) or the Golgi network. Post-translational adducts determine a differential responsiveness of Notch-expressing cells to the ligands. Thereafter, Notch receptor is cleaved at the level of the S1 cleavage site (S1) by a furin-like convertase residing in the trans-Golgi network. The cleavage results in the formation of a heterodimeric receptor, consisting of a Notch extracellular domain (NECD) and a Notch transmembrane domain (NTMD) held together by Ca2+-dependent ionic bonds [22, 23]. Similarly, also Notch ligand undergoes a “maturation process” consisting in its endocytosis, ubiquitination by the Neuralized and Mindbomb E3 ubiquitin ligases and “recycling” to the plasma membrane [24]. Notch ligands belong to the Delta/Serrate/LAG2 (DSL) protein family. After ligand binding, the mature Notch receptor is subjected to two successive proteolytic cleavages (S2 and S3 cleavage). The first cleavage is exerted by an ADAM metalloprotease (e.g. ADAM17) close the transmembrane domain to generate the Notch extracellular truncation (NEXT) fragment (S2 cleavage). The second is operated by the γ-secretase complex within the transmembrane domain of the NEXT fragment (S3 cleavage) or in endosomes, to dump into the cytoplasm the biologically active Notch intracellular domain (NICD) (reviewed in [11]). In the cell nucleus, NICD forms a trimeric complex with RBPJ and MAML1, which initiates transcription of Notch downstream target genes

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