Mos Protein Kinase Activation Requires Hsp90

Abstract

The protein kinase Mos activates the mitogen-activated protein kinase (MAPK) cascade that controls the meiotic maturation of oocytes. Although the mechanisms regulating the levels of Mos protein have been identified, the mechanisms regulating the kinase activity of Mos are unknown. Fisher, Mandart, and Dorée show that Mos phosphorylation and activation is inhibited in Xenopus oocytes by geldanamycin (GA), an inhibitor of Hsp90, which also blocks MAPK activation in Xenopus oocytes. GA treatment selectively blocked activation of Mos, not its increase in translation in response to hormonal activation of oocyte maturation. Injected mutated Mos, in which the serine that is phosphorylated upon activation is mutated to glutamate to mimic the phosphorylated state, failed to activate MAPK and to induce germinal vesicle breakdown when Hsp90 was inhibited, suggesting that phosphorylation alone was insufficient to activate Mos. Finally, glutathione S-transferase (GST) pull-down experiments were used to demonstrate the physical association of GST-Mos with Hsp70 and Hsp90. The authors suggest that Mos first interacts with Hsp70, then transiently with Hsp90, which leads to activation and reduced binding to Hsp70. Fisher, D.L., Mandart, E., and Dorée, M. (2000) Hsp90 is required for c-Mos activation and biphasic MAP kinase activation in Xenopus oocytes. EMBO J . 19 : 1516-1524. [Abstract] [Full Text]