Prostaglandins Eicosanoid Activates Ras Covalently

Prostaglandins are short-lived lipid species with diverse biological activities, including roles in inflammation, cell differentiation, proliferation, and apoptosis. Oliva et al. showed that the cyclopentenone prostaglandin 15-deoxy-^12,14-prostaglandin J₂ (15d-PGJ₂) stimulated phosphorylation and activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) and augmented the effects of serum on ERK and Akt phosphorylation and cell proliferation. Using cells overexpressing the three isoforms of Ras (H-Ras, K-Ras, or N-Ras), the authors showed that the stimulatory effects of 15d-PGJ₂ were mediated by stimulating guanosine triphosphate loading of H-Ras specifically. Mass spectrometry analysis and biotinylation experiments indicated that 15d-PGJ₂ covalently modified H-Ras. Modification at Cys¹⁸⁴ was confirmed by mutation to Ser, which reduced the incorporation of biotinylated 15d-PGJ₂ and blocked the ability of 15d-PGJ₂ to directly stimulate or potentiate serum stimulation of H-Ras activation or ERK phosphorylation. Thus, cyclopentenone prostaglandins may stimulate cell proliferation by adduction to H-Ras, stimulating its activity.

J. L. Oliva, D. Pérez-Sala, A. Castrillo, N. Martínez, F. J. Cañada, L. Boscá, J. M. Rojas, The cyclopentenone 15-deoxy-^12,14-prostaglandin J₂ binds to and activates H-Ras. Proc. Natl. Acad. Sci. U.S.A. 100, 4772-4777 (2003). [Abstract] [Full Text]

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VIRTUAL JOURNAL
The cyclopentenone 15-deoxy-^12,14-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 (15 April 2003)
PNAS 100 (8), 4772. [DOI: 10.1073/pnas.0735842100]
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