DIFFERENTIAL REGULATION OF C-JUN BY ERK AND JNK DURING PC12 CELL-DIFFERENTIATION

The two MAP kinases JNK and ERK direct distinct cellular activities ev en though they share a number of common substrates, including several transcription factors. Here we have compared JNK and ERK signalling du ring PC12 cell differentiation and investigated how activation of c-Ju n by the MAPKs contributes to this cellular response. Exposure to nerv e growth factor, or expression of constitutively active MEK1-two treat ments which cause differentiation of PC12 cells into a neuronal phenot ype-result in activation of ERK-type MAP kinases and phosphorylation o f c-Jun on several sites including Ser63 and Ser73, Constitutively act ivated c-Jun, which mimics the MAPK-phosphorylated form of the protein , can induce neuronal differentiation of PC12 cells independently of u pstream signals. Conversely, expression of dominant-negative c-Jun(bZI P) prevents neurite outgrowth induced by activated MEK1, Activation of MEKK1, which stimulates the JNK pathway, is not sufficient for PC12 c ell differentiation but can induce apoptosis, However, neurite outgrow th is triggered when c-Jun is co-expressed with activated MEKK1 or SEK 1, Consistently, MEK-induced ERK activation in PC12 cells induces c-Ju n expression, while JNK signalling does not. Therefore, dual input of expression and phosphorylation of c-Jun provided by the ERK pathway is required to direct neuronal differentiation in PC12 cells.