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First published online September 17, 2008
doi: 10.1242/10.1242/jcs.035683

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The molecular logic of Notch signaling – a structural and biochemical perspective

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA

^* Author for correspondence (e-mail: sblacklow{at}rics.bwh.harvard.edu)

Accepted 5 August 2008

The Notch signaling pathway constitutes an ancient and conserved mechanism for cell-cell communication in metazoan organisms, and has a central role both in development and in adult tissue homeostasis. Here, we summarize structural and biochemical advances that contribute new insights into three central facets of canonical Notch signal transduction: (1) ligand recognition, (2) autoinhibition and the switch from protease resistance to protease sensitivity, and (3) the mechanism of nuclear-complex assembly and the induction of target-gene transcription. These advances set the stage for future mechanistic studies investigating ligand-dependent activation of Notch receptors, and serve as a foundation for the development of mechanism-based inhibitors of signaling in the treatment of cancer and other diseases.

Key words: Biological signaling, Protein biochemistry, Receptor, Regulated intramembrane proteolysis, Transcription