Phosphatidylinositol 3-kinase translocates to the nucleus of osteoblast-like MC3T3-E1 cells in response to insulin-like growth factor I and platelet-derived growth factor but not to the proapoptotic cytokine tumor necrosis factor alpha

Changes in the metabolism of nuclear inositides phosphorylated in the D3 po sition of the inositol ring, which may act as second messengers, mainly hav e been linked to cell differentiation. To clarify a possible role of this p eculiar class of inositides also during cell proliferation and/or apoptosis , we have examined the issue of whether or not in the osteoblast-like clona l cell line MC3T3-E1 it may be observed an insulin-like growth factor-I (IG F-I)- and platelet-derived growth factor (PDGF)-dependent nuclear transloca tion of an active phosphatidylinositol 3-kinase (PI 3-K), We found that bot h the growth factors increased rapidly and transiently both the amount and the activity of immunoprecipitable nuclear PI 3-K. Intranuclear PI 3-K exhi bited a massive tyrosine phosphorylation on the p85 regulatory subunit, Mor eover, by means of coimmunoprecipitation experiments, we showed the presenc e, in isolated nuclei, of the p110 beta catalytic subunit of PI 3-K. Enzyme translocation was blocked by the specific PI 3-K inhibitor LY294002. In co ntrast, intranuclear translocation of PI 3-K did not occur in response to t he proapoptotic cytokine tumor necrosis factor alpha (TNF-alpha), IGF-I was able to counteract the apoptotic stimulus of TNF-alpha and this was accomp anied by the intranuclear translocation of PI 3-K. LY294002 inhibited both intranuclear translocation of PI 3-K and the rescuing effect of IGF-I, Thes e findings strongly suggest that an important step in the signaling pathway s that mediate both cell proliferation and survival is represented by the i ntranuclear translocation of PI 3-K.