A network of mitogen-activated protein kinases links G protein-coupled receptors to the c-jun promoter: a role for c-Jun NH2-terminal kinase, p38s, and extracellular signal-regulated kinase 5

The expression of the c-jun proto-oncogene is rapidly induced in response t o mitogens acting on a large variety of cell surface receptors, The resulti ng functional activity of c-Jun proteins appears to be critical for cell pr oliferation. Recently, we have shown that a large family of G protein-coupl ed receptors (GPCRs), represented by the mi muscarinic receptor, can initia te intracellular signaling cascades that result in the activation of mitoge n-activated protein kinases (MAPK) and c-Jun NH2-terminal kinases (JNK) and that the activation of JNK but not of MAPK correlated with a remarkable in crease in the expression of c-jun mRNA, Subsequently, however, we obtained evidence that GPCRs can potently stimulate the activity of the c-jun promot er through MEF2 transcription factors, which do not act downstream from JNK . In view of these observations, we set out to investigate further the natu re of the signaling pathway linking GPCRs to the c-jun promoter. Utilizing NIH 3T3 cells, we found that GPCRs can activate the c-jun promoter in a JNK -independent manner. Additionally, we demonstrated that these GPCRs can ele vate the activity of novel members of the MAPK family, including ERK5, p38 alpha, p38 gamma, and p38 delta, and that the activation of certain kinases acting downstream from MEK5 (ERK5) and MKK6 (p38 alpha and p38 gamma) is n ecessary to fully activate the c-jun promoter. Moreover, in addition to JNK , ERK5, p38 alpha, and p38 gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements. Taken together, these results s uggest that the pathway linking GPCRs to the c-jun promoter involves the in tegration of numerous signals transduced by a highly complex network of MAP K, rather than resulting from the stimulation of a single linear protein ki nase cascade. Furthermore, our findings suggest that each signaling pathway affects one or more regulatory elements on the c-jun promoter and that the transcriptional response most likely results from the temporal integration of each of these biochemical routes.