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| The EMBO Journal
(1998) 17, 4404–4413, doi:10.1093/emboj/17.15.4404 |
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| Differential regulation of c-Jun by ERK and JNK during PC12 cell differentiation |
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| Sirpa Leppä, Rainer Saffrich, Wilhelm Ansorge and Dirk Bohmann |
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European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany To whom correspondence should be addressed Dirk Bohmann, bohmann@EMBL-heidelberg.de Received 3 April 1998; Revised 2 June 1998; Accepted 4 June 1998. |
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| Abstract |
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| The two MAP kinases JNK and ERK direct distinct cellular activities even though they share a number of common substrates, including several transcription factors. Here we have compared JNK and ERK signalling during PC12 cell differentiation and investigated how activation of c-Jun by the MAPKs contributes to this cellular response. Exposure to nerve growth factor, or expression of constitutively active MEK1—two treatments which cause differentiation of PC12 cells into a neuronal phenotype—result in activation of ERK-type MAP kinases and phosphorylation of c-Jun on several sites including Ser63 and Ser73. Constitutively activated c-Jun, which mimics the MAPK-phosphorylated form of the protein, can induce neuronal differentiation of PC12 cells independently of upstream signals. Conversely, expression of dominant-negative c-JunbZIP prevents neurite outgrowth induced by activated MEK1. Activation of MEKK1, which stimulates the JNK pathway, is not sufficient for PC12 cell differentiation but can induce apoptosis. However, neurite outgrowth is triggered when c-Jun is co-expressed with activated MEKK1 or SEK1. Consistently, MEK-induced ERK activation in PC12 cells induces c-Jun 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. |
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| Keywords: c-Jun, differentiation, MAP kinases, phosphorylation, signal transduction |
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