Constitutive activation of the MAPK pathway mediates v-fes-induced mitogenesis in murine macrophages

Fes is a nonreceptor tyrosine kinase expressed at the highest level in macr ophages, We previously showed that the overexpression of c-fes in murine ma crophages of the BAC-1.2F5 cell line renders these cells independent of mac rophage colony-stimulating factor (MCSF) for survival and proliferation, al though no direct relationship could be established between tyrosine-phospho rylated substrates of Fes- and MCSF receptor-dependent signaling and mitoge nesis. In this study, we investigated whether the mitogen-activated protein kinase (MAPK) pathway is involved in the growth factor-independent growth of v-fes-overexpressing macrophages, We found a constitutively increased ph osphorylation of extracellularly regulated kinase (ERK) in v-fes-overexpres sing macrophages as compared with mock-infected cells. This finding was ass ociated with activation of nitrogen/extracellular signal-regulated kinase ( MEK) and with constitutive localization of ERK in the nucleus. Treatment of v-fes-overexpressing cells with the MEK-specific inhibitor PD98059 markedl y reduced cell growth, hyperphosphorylation, and nuclear localization of ER K, indicating that the MAPK pathway mediates the mitogenic effect of v-fes. (C) 2000 by The American Society of Hematology.