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J. Biol. Chem., Vol. 277, Issue 26, 23949-23957, June 28, 2002

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Activation of c-Raf Kinase by Ultraviolet Light
REGULATION BY RETINOIDS^*

Beatrice Hoyos, Asiya Imam, Irina Korichneva, Ester Levi, Ramon Chua, and Ulrich Hammerling

From the Immunology Program, Memorial Sloan-Kettering Cancer Center, New York 10021

The present study highlights retinoids as modulators of c-Raf kinase activation by UV light. Whereas a number of retinoids, including retinol, 14-hydroxyretroretinol, anhydroretinol (AR), and retinoic acid bound the c-Raf cysteine-rich domain (CRD) with equal affinity in vitro as well as in vivo, they displayed different, even opposing, effects on UV-mediated kinase activation; retinol and 14-hydroxyretroretinol augmented responses, whereas retinoic acid and AR were inhibitory. Oxidation of thiol groups of cysteines by reactive oxygen, generated during UV irradiation, was the primary event in c-Raf activation, causing the release of zinc ions and, by inference, a change in CRD structure. Retinoids modulated these oxidation events directly: retinol enhanced, whereas AR suppressed, zinc release, precisely mirroring the retinoid effects on c-Raf kinase activation. Oxidation of c-Raf was not sufficient for kinase activation, productive interaction with Ras being mandatory. Further, canonical tyrosine phosphorylation and the action of phosphatase were essential for optimal c-Raf kinase competence. Thus, retinoids bound c-Raf with high affinity, priming the molecule for UV/reactive oxygen species-mediated changes of the CRD that set off GTP-Ras interaction and, in context with an appropriate phosphorylation pattern, lead to full phosphotransferase capacity.

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