Platelet-derived growth factor-induced signaling pathways interconnect to regulate the temporal pattern of Erk1/2 phosphorylation

The biological outcome of Erk1/2 activation is specified by the duration and magnitude of its phosphorylation, as well as its subcellular localization. In the present study, we investigated how the cross-talk between signaling pathways induced by platelet-derived growth factor receptor β (PDGFRβ) regulates the temporal pattern of Erk1/2 activation. We demonstrated that Src kinase activity was necessary for rapid Erk1/2 phosphorylation in PDGF-BB-stimulated cells. A delay in the onset of Erk1/2 activation was also observed upon phospholipase C (PLC) inhibition; this effect was found to be mediated by protein kinase C (PKC). In addition, we observed that both the PI3K pathway and RasGAP negatively regulated the strength of Erk1/2 phosphorylation. In contrast, interfering with SHP2 binding to PDGFRβ did not affect the pattern of Erk1/2 activation. Interestingly, changes in the kinetics and amplitude of Erk1/2 activation were transmitted to the transcriptional level and affected c-fos expression. In conclusion, cross-talk with other PDGFRβ-induced signaling pathways is important for fine-tuning of the pattern of Erk1/2 activation.