Functional interaction between RAFT1/FRAP/mTOR and protein kinase C delta in the regulation of cap-dependent initiation of translation

Hormones and growth th factors induce protein translation in Dart by phosph orylation of the eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1). The rapamycin and FK506-binding protein (FKBP-)target 1 (RAFT1, a lso known as FRAP) is a mammalian homolog of the Saccharomyces cerevisiae t arget of rapamycin proteins (mTOR) that regulates 4E-BP1. However, the mole cular mechanisms involved in growth factor-initiated phosphorylation of 4E- BP1 are not well understood. Here we demonstrate that protein kinase C delt a (PKC delta) associates with RAFT1 and that PKC delta is required for the phosphorylation and inactivation of 4E-BP1. PKC delta-mediated phosphorylat ion of 4E-BP1 is wortmannin resistant but rapamycin sensitive. As shown for serum, phosphorylation of 4E-BP1 by PKC delta inhibits the interaction bet ween 4E-BP1 and eIF4E and stimulates cap-dependent translation. Moreover, a dominant-negative mutant of PKC delta inhibits serum-induced phosphorylati on of 4E-BP1. These findings demonstrate that PKC delta associates with RAF T1 and thereby regulates phosphorylation of 4E-BP1 and cap-dependent initia tion of protein translation.