Evidence for MEK-independent pathways regulating the prolonged activation of the ERK-MAP kinases

The mitogen-activated protein kinases (MAPKs) ERK-1 and ERK-2 are activated by a wide variety of oncogenes and extracellular stimuli. The MAPKs participate in a signalling cascade downstream of growth factor/cytokine receptors, Ras, Raf, and MEK. However, MAPK activation is more complicated than a simple linear pathway, and the evidence presented here supports a model of multiple, temporally distinct pathways converging on MAPK which are differentially utilized by various stimuli and cell types. In addition to MEK-dependent MAPK activation, we provide evidence for MEK-independent regulation of the MAPKs. Our results suggest that phosphatidylinositol-3-kinases (PI(3)K) or conventional protein kinase C isoforms (cPKCs) partially contribute to MEK-dependent activation. Importantly, we also find that PI3K and cPKCs play a major role in the MEK-independent, prolonged MAPK activation by platelet-derived growth factor signalling. This finding is of interest as the maintained activation of MAPK has been correlated by others to the regulation of cell proliferation and differentiation.