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 journalArticle

56 Citations (Scopus)

Abstract

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
Volume170
Issue number5
DOIs
StatePublished - Aug 2005
Externally publishedYes

Fingerprint

Ligases
Ubiquitin
Proteins
Cullin Proteins
Photobleaching
Cues
Membrane Proteins

ASJC Scopus subject areas

  • Cell Biology

Cite this

Mekhail, K., Khacho, M., Carrigan, A., Hache, R. R. J., Gunaratnam, L., & Lee, S. (2005). Regulation of ubiquitin ligase dynamics by the nucleolus. Journal of Cell Biology, 170(5), 733-744. https://doi.org/10.1083/jcb.200506030

Regulation of ubiquitin ligase dynamics by the nucleolus. / Mekhail, Karim; Khacho, Mireille; Carrigan, Amanda; Hache, Robert R J; Gunaratnam, Lakshman; Lee, Stephen.

In: Journal of Cell Biology, Vol. 170, No. 5, 08.2005, p. 733-744.

Research output: Contribution to journalArticle

Mekhail, K, Khacho, M, Carrigan, A, Hache, RRJ, Gunaratnam, L & Lee, S 2005, 'Regulation of ubiquitin ligase dynamics by the nucleolus', Journal of Cell Biology, vol. 170, no. 5, pp. 733-744. https://doi.org/10.1083/jcb.200506030
Mekhail K, Khacho M, Carrigan A, Hache RRJ, Gunaratnam L, Lee S. Regulation of ubiquitin ligase dynamics by the nucleolus. Journal of Cell Biology. 2005 Aug;170(5):733-744. https://doi.org/10.1083/jcb.200506030
Mekhail, Karim ; Khacho, Mireille ; Carrigan, Amanda ; Hache, Robert R J ; Gunaratnam, Lakshman ; Lee, Stephen. / Regulation of ubiquitin ligase dynamics by the nucleolus. In: Journal of Cell Biology. 2005 ; Vol. 170, No. 5. pp. 733-744.
@article{c3bdfd26fd594f5288b0d62156353c15,
title = "Regulation of ubiquitin ligase dynamics by the nucleolus",
abstract = "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.",
author = "Karim Mekhail and Mireille Khacho and Amanda Carrigan and Hache, {Robert R J} and Lakshman Gunaratnam and Stephen Lee",
year = "2005",
month = "8",
doi = "10.1083/jcb.200506030",
language = "English (US)",
volume = "170",
pages = "733--744",
journal = "Journal of Cell Biology",
issn = "0021-9525",
publisher = "Rockefeller University Press",
number = "5",

}

TY - JOUR

T1 - Regulation of ubiquitin ligase dynamics by the nucleolus

AU - Mekhail, Karim

AU - Khacho, Mireille

AU - Carrigan, Amanda

AU - Hache, Robert R J

AU - Gunaratnam, Lakshman

AU - Lee, Stephen

PY - 2005/8

Y1 - 2005/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=24144477311&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24144477311&partnerID=8YFLogxK

U2 - 10.1083/jcb.200506030

DO - 10.1083/jcb.200506030

M3 - Article

VL - 170

SP - 733

EP - 744

JO - Journal of Cell Biology

JF - Journal of Cell Biology

SN - 0021-9525

IS - 5

ER -