Multiple signaling pathways are involved in the regulation of IGF-I receptor inhibition of PTEN-enhanced apoptosis.

ABSTRACT

PTEN is a dual protein and lipid phosphatase that dephosphorylates PIP3 at the 3' position, thereby antagonizing PI3-kinase activity. A reduction in PI3' kinase activity enhances the susceptibility of cells to apoptosis. By stably transfecting PC12 cells with an antisense PTEN construct, endogenous PTEN protein levels were reduced by approximately 50% and etoposide-induced apoptosis was markedly decreased. Furthermore, IGF-I receptor abrogation of this apoptotic effect was inhibited by both PI3' kinase and by specific inhibitors of p38 MAP kinase. Thus, we show for the first time that p38 MAP kinase is involved in this process.