Notch -- a goldilocks signaling pathway in disease and cancer therapy.
The Notch signaling pathway is a fundamental signaling mechanism operating in most, if not all, multicellular organisms and in most cell types in the body. Like other "ivy league" pathways such as Wnt, PI3K, Sonic Hedgehog, Receptor Tyrosine Kinases (RTKs), and JAK/STAT signaling, the Notch pathway is a linear signaling mechanism, i.e., an extracellular ligand activates a receptor, which ultimately leads to transcriptional alterations in the cell nucleus, but Notch signaling is a strict cell-cell communication mechanism and lacks built-in amplification steps in the signaling pathway. Dysregulated Notch signaling, either by direct mutations in the pathway or by altered signaling output, is increasingly linked to disease, and Notch can act as an oncogene or tumor suppressor depending on the cellular context. This underscores that appropriate level of Notch signaling is important for differentiation and tissue homeostasis, a notion supported also by genetic data indicating that Notch signaling is very gene dosage-sensitive. Thus, too much or too little signaling can lead to disease and Notch can therefore be considered a Goldilocks signaling pathway. Given the emerging role of dysregulated Notch signaling in disease, there is increasing interest in developing therapeutic approaches to modulate Notch signaling. In this review we discuss recent findings on how signal transduction is tuned in the Notch pathway and how Notch signaling is dysregulated in disease. We also discuss different strategies to modulate Notch signaling for clinical use, for example by novel antibody-based tools and by taking advantage of the cross-talk between Notch and other signaling mechanisms.
Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
Eike-Benjamin
EB
Braune
Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
Urban
U
Lendahl
D016738:Alagille Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000906:Antibodies / Q000627:therapeutic use*; D001021:Aortic Valve / Q000473:pathology; D046589:CADASIL / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D004359:Drug Therapy, Combination; D006349:Heart Valve Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
D000906:Antibodies; D051880:Receptors, Notch; D019869:Phosphatidylinositol 3-Kinases; D053829:Amyloid Precursor Protein Secretases