Editors' ChoiceProstaglandins

Eicosanoid Activates Ras Covalently

Science's STKE  22 Apr 2003:
Vol. 2003, Issue 179, pp. tw157-TW157
DOI: 10.1126/stke.2003.179.tw157

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-Δ12,14-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-Δ12,14-prostaglandin J2 binds to and activates H-Ras. Proc. Natl. Acad. Sci. U.S.A. 100, 4772-4777 (2003). [Abstract] [Full Text]