TI - 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 3T3 cells . AB - The initiation factor (eIF) 4E is regulated by modulating both the phosphorylation and the availability of the protein to participate in the initiation process . Here we show that either serum treatment or activation of the stress-activated protein kinase (JNK/SAPK) led to enhanced phosphorylation of eIF4E in quiescent NIH 3T3 cells . Although the immunosuppressant , rapamycin , was found to stabilize the association of eIF4E with its negative regulator , 4E-BP1 , this drug did not prevent the early effects of serum stimulation on the overall rate of translation , polysome formation , the phosphorylation status of eIF4E , or the recruitment of eIF4E into the eIF4F complex . However , the rapid enhancement of eIF4E phosphorylation in response to serum was largely prevented by the inhibitor of mitogen-activated protein ( MAP ) kinase activation , PD98059 . Activation of the JNK/SAPK signaling pathway with anisomycin resulted in enhanced phosphorylation of eIF4E , which was prevented by either rapamycin or the highly specific p38 MAP kinase inhibitor , SB203580 . These data illustrate that multiple signaling pathways , including 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 .