Category: signaling
Notch is a juxtacrine cell-cell signaling system — short-range, contact-dependent — that controls binary cell-fate decisions and lateral inhibition. Four mammalian receptors (Notch1–4) + five DSL ligands (Delta-like 1/3/4, Jagged1/2). Mechanism: receptor and ligand are both transmembrane on adjacent cells. Ligand-receptor binding pulls the Notch extracellular domain off → exposes S2 cleavage site for ADAM10/17 (TACE) → produces a substrate for γ-secretase (the same complex that cleaves APP — relevant to Alzheimer pharmacology). γ-secretase performs S3 cleavage in the transmembrane domain → releases the Notch intracellular domain (NICD) → NICD translocates to nucleus → binds CSL (CBF-1/RBP-Jκ in mammals) → recruits MAML coactivator + p300 → activates Notch target genes (HES, HEY families — basic-helix-loop-helix repressors of differentiation programs). Output: maintains stem/progenitor states; drives lineage choice (e.g., T-cell vs B-cell at thymic entry; absorptive vs secretory enterocyte; arterial vs venous endothelial). Cancer relevance: NOTCH1 gain-of-function in ~50% of T-ALL (γ-secretase inhibitors trialed); NOTCH3 in vascular CADASIL; oncogene in some solid tumors but tumor suppressor in others (skin SCC). Therapeutics: γ-secretase inhibitors (GSIs — once trialed in Alzheimer for APP-cleavage; failed due to Notch-mediated GI toxicity — goblet-cell metaplasia from disrupted intestinal differentiation); anti-DLL3 (rovalpituzumab) for SCLC; anti-Notch1 antibody Brontictuzumab. Cross-links: [[cell_cycle_cdk]] (proliferation control), [[wnt_beta_catenin]] (parallel/contrasting morphogen), [[hedgehog_smoothened]] (parallel).