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Sci. Signal., 21 September 2010
Vol. 3, Issue 140, p. ra68
[DOI: 10.1126/scisignal.20001370]

RESEARCH ARTICLES

Regulation of Ras Localization by Acylation Enables a Mode of Intracellular Signal Propagation

Anna Lorentzen1,2, Ali Kinkhabwala3, Oliver Rocks1,4, Nachiket Vartak3, and Philippe I. H. Bastiaens1,3,5*

1 European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
2 Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
3 Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
4 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5.
5 Technische Universität Dortmund, Fachbereich Chemie, 44227 Dortmund, Germany.

Abstract: Growth factor stimulation generates transient H-Ras activity at the plasma membrane but sustained activity at the Golgi. Two overlapping regulatory networks control compartmentalized H-Ras activity: the guanosine diphosphate–guanosine triphosphate cycle and the acylation cycle, which constitutively traffics Ras isoforms that can be palmitoylated between intracellular membrane compartments. Quantitative imaging of H-Ras activity after decoupling of these networks revealed regulation of H-Ras activity at the plasma membrane but not at the Golgi. Nevertheless, upon stimulation with epidermal growth factor, Ras activity at the Golgi displayed a pulse-like profile similar to that at the plasma membrane but also remained high after the initial stimulus. A compartmental model that included the acylation cycle and H-Ras regulation at the plasma membrane accounted for the pulse-like profile of H-Ras activity at the Golgi but implied that sustained H-Ras activity at the Golgi required H-Ras activation at an additional compartment, which we experimentally determined to be the endoplasmic reticulum. Thus, in addition to maintaining the localization of Ras, the acylation cycle underlies a previously unknown form of signal propagation similar to radio transmission in its generation of a constitutive Ras "carrier wave" that transmits Ras activity between subcellular compartments.

* To whom correspondence should be addressed. E-mail: philippe.bastiaens{at}mpi-dortmund.mpg.de

Citation: A. Lorentzen, A. Kinkhabwala, O. Rocks, N. Vartak, P. I. H. Bastiaens, Regulation of Ras Localization by Acylation Enables a Mode of Intracellular Signal Propagation. Sci. Signal. 3, ra68 (2010).

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