WORTMANNIN, AN INHIBITOR OF PHOSPHATIDYL-INOSITOL 3-KINASE, INDUCES OOCYTE MATURATION THROUGH A MPF-MAPK-DEPENDENT PATHWAY

Wortmannin has been shown to be a non-competitive and irreversible inh ibitor of PI3 kinase. For this reason, it has attracted considerable i nterest and it has been used, as a selective inhibitor of the PI3 kina se, for the study of signal transduction pathways in different systems including Xenopus oocytes. We show here that wortmannin itself is abl e to induce meiotic maturation at doses slightly higher that those req uired for complete inhibition of PI3 kinase. This effect was shown to be independent of the ability to inhibit PI3K since another unrelated PI3K inhibitor, LY294002, was unable to induce oocyte maturation at in hibitory concentrations for PI3 kinase. The mechanism for wortmannin-i nduced maturation involves the activation of maturation promoting fact or (MPF) and MAP kinase activities in a time course that preceded the appearance of germinal vesicle breakdown. Thus, the pathway activated by wortmannin directly or indirectly affects other protein or proteins , besides PI3 kinase, responsible for its activity. This new target is placed independently or downstream of the PI3 kinase inhibition and u pstream of protein synthesis. Moreover, the inhibition of either MPF o r cAMP phosphodiesterase blocks wortmannin-induced maturation. We conc lude that wortmannin may be a valuable tool for the study of the pathw ay leading to mitotic maturation of oocytes, but cannot be used as a s pecific PI3 kinase inhibitor. (C) 1998 Federation of European Biochemi cal Societies.