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Fig. 1 | Journal of Hematology & Oncology

Fig. 1

From: The Notch signaling pathway: a potential target for cancer immunotherapy

Fig. 1

The Notch signaling pathway. A-B Composition of five Notch ligands (Jagged1, Jagged2, Dll1, Dll3, and Dll4) and four Notch receptors (Notch1, Notch2, Notch3, and Notch4). Each domain of Notch ligands and receptors is shown. The structures of Notch1-4 are highly homologous but show differences to certain extents. All of the four receptors have the same or similar LNR, HD, TMD, RAM, NLS, ANK, and PEST. The protein structures of Notch1 and Notch2 are highly similar, both of which have 36 EGF repeats in their NECDs. Compared with Notch1/2, Notch3 has 34 EGF repeats and lacks TAD structure, while Notch4 has only 29 EGF repeats and also lacks the TAD structure. SP: Signal peptide; MNNL: Module at N-terminal domain of Notch ligand; DSL: Delta, Serrate, and LAG-2 domain; DOS: Delta and OSM-11-like proteins domain; CR: Cysteine-rich domain; TMD: Transmembrane domain; PDZ: PDZ domain; LNR: Lin 12-Notch repeats; HD: Heterodimerization domain; RAM: RBP-J association module; NLS: Nuclear localization sequences; ANK: Ankyrin repeats; TAD: Transcription activation domain. PEST: proline, glutamic acid, serine, threonine-rich domain. C. Activation of Notch signaling: ①: Notch receptors are synthesized and processed in the ER and Golgi apparatus and then transported to the cell membrane to form heterodimers; ② and ③: Notch ligands from signal-sending cells bind to the NECD of signal-receiving cells. The binding triggers cleavage by ADAM and then γ-secretase, which releases activated NICD; ④ and ⑤: Activated NICD enters the nucleus and binds to MAML, RBP-J, and other proteins to form transcription complexes that promote the transcription of a series of genes (e.g., Hes1, Hey1) through RBP-J-dependent canonical Notch signaling; ⑥: Activated NICD directly activates the expression of a series of genes (e.g., PI3K/AKT) through RBP-J-independent non-canonical signaling. The six yellow rectangular boxes (a-f) represent clinically or preclinically used inhibitors, blocking antibodies, or target gene’s antisense oligonucleotides (ASOs) that inhibit Notch signaling. They are mainly: (a) inhibitors that inhibit the formation of Notch receptors (e.g., SERCA inhibitor); (b-c) antibodies that inhibit Notch receptors or ligands [e.g., OMP-52M51 (anti-Notch1), OMP-59R5 (anti-Notch2/3), MEDI0639 (anti-Dll4), Demcizumab (anti-Dll4), and CTX014 (anti-Jagged1/2)], and receptor’s or ligand’s ASOs; (d-e) ADAM inhibitors or γ-secretase inhibitors that inhibit the cleavage of Notch receptor (e.g., INCB7839, ZLDI-8, AL101, and MK0752); (f) Inhibitors that inhibit transcriptional complexes (e.g., CB-103, SAHM1, and IMR-1) and target gene’s ASOs. mAbs: monoclonal antibodies. Asterisks (*) indicate drugs that are being assessed in clinical trials. Figure was created with BioRender.com

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