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PNAS 100 (8): 4772-4777

Copyright © 2003 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

The cyclopentenone 15-deoxy-{Delta}12,14-prostaglandin J2 binds to and activates H-Ras

José Luis Oliva*,{dagger}, Dolores Pérez-Sala{dagger},{ddagger},§, Antonio Castrillo{dagger},¶, Natalia Martínez*, F. Javier Cañada{ddagger}, Lisardo Boscá, and José M. Rojas*,§

*Unidad de Biología Celular, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain; {ddagger}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

Received for publication September 26, 2002.

Abstract: The cyclopentenone 15-deoxy-{Delta}12,14-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.

Key Words: mitogen-activated protein kinase||cell proliferation||posttranslational modification

{dagger} J.L.O., D.P.-S., and A.C. contributed equally to this work.

§ To whom correspondence should be addressed. E-mail: dperezsala{at}cib.csic.es or jmrojas{at}isciii.es.

Edited by Edward M. Scolnick, Merck & Co., Inc., West Point, PA, and approved February 7, 2003

This paper was submitted directly (Track II) to the PNAS office.

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