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Targeting Notch in Cancer pp 1–33Cite as

Structural Biology of Notch Signaling

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Abstract

The conserved Notch signaling pathway plays a central role in development and adult tissue homeostasis. Notch signaling is initiated by binding to a transmembrane ligand. E3 ubiquitin ligase-mediated ligand endocytosis enables release of the negative regulatory region (NRR) of Notch from autoinhibition, which then allows metalloprotease cleavage within the NRR, followed by intramembrane cleavage by the γ-secretase complex. After release from the membrane, the Notch intracellular domain translocates to the nucleus to form a transcriptionally active complex and initiate transcription of Notch-responsive genes. Structural studies of Notch and Notch-associated molecules, which have advanced our understanding of each of these steps in the Notch signaling pathway, are reviewed here.

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Note added in proof

Since this chapter was written, a structure of a JAG1-Notch1 complex was reported (V.C. Luca et al., Science 10.1126/science.aaf9739;2017), the structure of an ADAM10 ectodomain was reported (T.C.M. Seegar et al., Cell 171, 1638–1648.e7;2017), and new structures of DLL4 and JAG2 isolated ligand fragments were reported (Suckling, R.J., et al. EMBO J 36(15): 2204–2215;2017).

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Authors and Affiliations

  1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    Kelly L. Arnett, Tom C. M. Seegar & Stephen C. Blacklow

  2. Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA

    Kelly L. Arnett, Tom C. M. Seegar & Stephen C. Blacklow

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  1. Kelly L. Arnett
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  3. Stephen C. Blacklow
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Correspondence to Stephen C. Blacklow .

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  1. Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Lucio Miele

  2. Department of Cell Biology, Harvard Medical School, Boston, MA, USA

    Spyros Artavanis-Tsakonas

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Arnett, K.L., Seegar, T.C.M., Blacklow, S.C. (2018). Structural Biology of Notch Signaling. In: Miele, L., Artavanis-Tsakonas, S. (eds) Targeting Notch in Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-8859-4_1

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