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More complicated than it looks: assembly of Notch pathway transcription complexes

Oncogene volume 27, pages 5099–5109 (2008)Cite this article

Abstract

The Notch pathway is a short-range signaling mechanism between neighboring cells that results in changes in gene expression. Extracellular interactions between Notch receptors and ligands trigger proteolytic cleavage of the receptor Notch. Following cleavage, the freed intracellular domain of Notch (NotchIC) moves from the cytoplasm to the nucleus, engaging the DNA-binding transcription factor CBF-1, Su(H), Lag-1 (CSL)—the nuclear effector of the pathway. NotchIC, together with the transcriptional coactivator Mastermind, form a ternary complex with CSL that activates transcription from genes that are responsive to Notch signaling. Illuminating the molecular details that underlie formation of the transcriptionally active CSL–NotchIC–Mastermind ternary complex is key for understanding how genes are turned on in response to a Notch signal. Recently, several studies using biophysical and computational methods have scrutinized how the CSL–NotchIC–Mastermind ternary complex forms and the role individual domains play in this process. These detailed analyses have provided a wealth of molecular insights into the assembly of a Notch pathway active transcription complex but have also raised several intriguing, yet confounding questions. This review will focus on the findings of these recent biophysical studies and provide speculative models that address these unanswered questions.

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Acknowledgements

I thank the members of my laboratory for the stimulating discussions regarding Notch signaling, which spurred the writing of this review. In particular, I thank Jeffrey Wilson and David Friedmann for editing the manuscript and assistance with creation of the figures. I am also very grateful for the biophysical expertise and constructive criticism provided by my departmental colleagues Andrew Herr and Tom Thompson. This work was supported by grants from the NIH and the University of Cincinnati Barrett Cancer Center.

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  1. Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    R A Kovall

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Correspondence to R A Kovall.

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Kovall, R. More complicated than it looks: assembly of Notch pathway transcription complexes. Oncogene 27, 5099–5109 (2008). https://doi.org/10.1038/onc.2008.223

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