THE EFFECT OF CYCLIC ADENOSINE-MONOPHOSPHATE ON THE MITOGEN-ACTIVATEDPROTEIN-KINASE PATHWAY DEPENDS ON BOTH THE CELL-TYPE AND THE TYPE OF TYROSINE KINASE-RECEPTOR

The mitogen-activated protein kinase (MAP kinase) is a key participant in growth factor-stimulated intracellular events such as proliferatio n and differentiation. We and others have previously described a cross -talk between the MAP kinase pathway and the cAMP pathway. Indeed, in several cell lines and, in particular in fibroblasts, an increase in t he level of cAMP produced an inhibition of MAP kinase together with de creased cell proliferation. In contrast, in PC12 cells, cAMP induced a n increase in the NGF-induced activation of MAP kinase concomitantly w ith augmented NGF-induced differentiation. Therefore, it has been prop osed that the cellular context is important for the nature of the cAMP effects on growth factor-stimulated MAP kinase activity. Here we show that the type of tyrosine kinase receptor stimulated also participate s in the nature of the cAMP effect. Thus, in NIH3T3 fibroblasts expres sing NGF receptors (NIH3T3/trk cells) we found that cAMP potentiates N GF-stimulated ERK1 and MEK1 activities, whereas in NIH3T3 fibroblasts expressing insulin receptors (NIH3T3/IR cells) we saw no effect of cAM P on the activation of insulin-stimulated ERK1 and MEK1. In PC12 cells and in Rat1 fibroblasts expressing insulin receptors (PC12/IR and Rat 1/IR cells) we observed, respectively, a potentiation and an inhibitio n of insulin-stimulated ERK1 activity. In addition, cAMP does not seem to modify the basal nor growth factor-stimulated She or IRS-1 tyrosin e phosphorylation in the different cell lines studied. Finally, we obs erved that cAMP inhibited serum- and insulin-induced, but not NGF-indu ced, cell proliferation in NIH3T3 cells. However, cAMP potentiated ins ulin-stimulated cell differentiation in PC12/IR cells. These results l ed us to conclude that the cAMP effect on cell proliferation in NIH3T3 fibroblasts and PC12/IR cells appears to be correlated, in part, with the effect of cAMP on the MAP kinase pathway, but by itself this path way cannot fully account for these observations.