The cyclopentenone 15-deoxy-Δ12,14-prostaglandin J2 binds to and activates H-Ras
- José Luis Oliva*,†,
- Dolores Pérez-Sala†,‡,§,
- Antonio Castrillo†,¶,
- Natalia Martínez*,
- F. Javier Cañada‡,
- Lisardo Boscá¶, and
- José M. Rojas*,§
- *Unidad de Biología Celular, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain; ‡Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28006 Madrid, Spain; and ¶Instituto de Bioquímica and Centro Nacional de Investigaciones Cardiovasculares, Centro Mixto Consejo Superior de Investigaciones Científicas–Universidad Complutense de Madrid, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
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Edited by Edward M. Scolnick, Merck & Co., Inc., West Point, PA, and approved February 7, 2003 (received for review September 26, 2002)
Abstract
The cyclopentenone 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) induces cell proliferation and mitogen-activated protein kinase activation. Here, we describe that these effects are mediated by 15d-PGJ2-elicited H-Ras activation. We demonstrate that this pathway is specific for H-Ras through the formation of a covalent adduct of 15d-PGJ2 with Cys-184 of H-Ras, but not with N-Ras or K-Ras. Mutation of C184 inhibited H-Ras modification and activation by 15d-PGJ2, whereas serum-elicited stimulation was not affected. These results describe a mechanism for the activation of the Ras signaling pathway, which results from the chemical modification of H-Ras by formation of a covalent adduct with cyclopentenone prostaglandins.
Footnotes
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↵ † J.L.O., D.P.-S., and A.C. contributed equally to this work.
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↵ § To whom correspondence should be addressed. E-mail: dperezsala{at}cib.csic.es or jmrojas{at}isciii.es.
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This paper was submitted directly (Track II) to the PNAS office.
- Abbreviations:
- 15d-PGJ2,
- 15-deoxy-Δ12,14-prostaglandin J2;
- PG,
- prostaglandin;
- CyPG,
- cyclopentenone PGs;
- MAPK,
- mitogen-activated protein kinase;
- COX-2,
- cyclooxygenase 2;
- ERK,
- extracellular signal-regulated kinase;
- PI3-kinase,
- phosphatidylinositol 3-kinase;
- HRP,
- horseradish peroxidase;
- HA,
- hemagglutinin
- Copyright © 2003, The National Academy of Sciences
