Regulation of ubiquitin ligase dynamics by the nucleolus

Karim Mekhail, Mireille Khacho, Amanda Carrigan, Robert R.J. Hache, Lakshman Gunaratnam, Stephen Lee

Research output: Contribution to journalArticlepeer-review

67 Scopus citations


Cellular pathways relay information through dynamic protein interactions. We have assessed the kinetic properties of the murine double minute protein (MDM2) and von Hippel-Lindau (VHL) ubiquitin ligases in living cells under physiological conditions that alter the stability of their respective p53 and hypoxia-inducible factor substrates. Photobleaching experiments reveal that MDM2 and VHL are highly mobile proteins in settings where their substrates are efficiently degraded. The nucleolar architecture converts MDM2 and VHL to a static state in response to regulatory cues that are associated with substrate stability. After signal termination, the nucleolus is able to rapidly release these proteins from static detention, thereby restoring their high mobility profiles. A protein surface region of VHL's β-sheet domain was identified as a discrete [H+]-responsive nucleolar detention signal that targets the VHL/Cullin-2 ubiquitin ligase complex to nucleoli in response to physiological fluctuations in environmental pH. Data shown here provide the first evidence that cells have evolved a mechanism to regulate molecular networks by reversibly switching proteins between a mobile and static state.

Original languageEnglish (US)
Pages (from-to)733-744
Number of pages12
JournalJournal of Cell Biology
Issue number5
StatePublished - Aug 2005
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology


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