INVOLVEMENT OF STRESS-ACTIVATED PROTEIN-KINASE AND P38 RK MITOGEN-ACTIVATED PROTEIN-KINASE SIGNALING PATHWAYS IN THE ENHANCED PHOSPHORYLATION OF INITIATION-FACTOR 4E IN NIH 3T9 CELLS/

The initiation factor (eIF) 4E is regulated by modulating both the pho sphorylation and the availability of the protein to participate in the initiation process. Here we show that either serum treatment or activ ation of the stress-activated protein kinase (JNK/SAPK) led to enhance d phosphorylation of eIF4E in quiescent NIH 3T3 cells, Although the im munosuppressant, rapamycin, was found to stabilize the association of eIF4E with its negative regulator, 4E-BP1, this drug did not prevent t he early effects of serum stimulation on the overall rate of translati on, polysome formation, the phosphorylation status of eIF4E, or the re cruitment of eIF4E into the eIF4F complex. However, the rapid enhancem ent of eIF4E phosphorylation in response to serum was largely prevente d by the inhibitor of mitogen-activated protein (MAP) kinase activatio n, PD98059. Activation of the JNK/SAPK signaling pathway with anisomyc in resulted in enhanced phosphorylation of eIF4E, which was prevented by either rapamycin or the highly specific p38 MAP kinase inhibitor, S B203580. These data. illustrate that multiple signaling pathways, incl uding those of distinct members of the MAP kinase family, mediate the phosphorylation of eIF4E and that the association of eIF4E with 4E-BP1 does not necessarily prevent phosphorylation of eIF4E in vivo.