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Nedd8 on cullin: building an expressway to protein destruction

Oncogene volume 23, pages 1985–1997 (2004)Cite this article

Abstract

This review summarizes recent advances concerning the Nedd8 regulatory pathway in four areas. One, substantial progress has been made in delineating the role of cullin family proteins, the only known substrates of the Nedd8 modification system. Cullins are molecular scaffolds responsible for assembling the ROC1/Rbx1 RING-based E3 ubiquitin ligases, of which several play a direct role in tumorigenesis. Two, a large body of work has helped elucidate the molecular details underlying the Nedd8 modification reaction, which results in covalent conjugation of a Nedd8 moiety onto a conserved cullin lysine residue. Three, studies using a variety of genetic model systems have established an essential role for Nedd8 in cell cycle control and in embryogenesis by upregulating the activities of cullin-based E3 ligases. In vitro experiments have revealed a direct role for Nedd8 in activating ubiquitination. Construction of a model of the ROC1/Rbx1-CUL1-Nedd8 structure suggests a mechanism by which the cullin-linked Nedd8 may assist the neighboring ROC1/Rbx1 in landing and positioning the E2 conjugating enzyme for the ubiquitin transfer reaction. Finally, increasing evidence indicates that removal of Nedd8 from its cullin targets, by the action of COP9 Signalosome and possibly other proteases, plays a significant role in the regulation of cullin-mediated proteolysis.

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Acknowledgements

We thank A Capili for assistance in the preparation of Figure 2b; W Gu for communication of unpublished data and F Miller for a critical reading of the manuscript. AK is a graduate trainee in the laboratory of K Borden who is supported by NIH Grants CA 80728 and CA 88991. We apologize to those whose works on Nedd8 have not been cited here due to space restrictions. The studies carried out in the Pan laboratory were supported by Public Health Service Grants GM61051 and CA095634.

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  1. Derald H Ruttenberg Cancer Center, The Mount Sinai School of Medicine, New York, 10029-6574, NY, USA

    Zhen-Qiang Pan, Dora C Dias, Kosj Yamoah & Kenneth Wu

  2. Department of Physiology and Biophysics, The Mount Sinai School of Medicine, New York, 10029-6574, NY, USA

    Alex Kentsis

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Pan, ZQ., Kentsis, A., Dias, D. et al. Nedd8 on cullin: building an expressway to protein destruction. Oncogene 23, 1985–1997 (2004). https://doi.org/10.1038/sj.onc.1207414

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