Abstract
ERK5 (also known as BMK1), a member of the mitogen-activated protein kinase (MAPK) superfamily, was known to be activated strongly by oxidant and osmotic stresses. Here we have found that ERK5 is strongly activated by epidermal growth factor and nerve growth factor, whose receptors are tyrosine kinases. The activation of ERK5 was inhibited by expression of dominant-negative Ras and induced by expression of active Ras in PC12 cells, indicating a requirement for Ras in ERK5 activation. The epidermal growth factor-induced activation of ERK5 was found to be inhibited by PD98059 and U0126 inhibitors, which were previously thought to act specifically on classical MAPK kinase (also known as MEK1) and readily reversed by CL100 and MKP-3 dual-specificity phosphatases for which classical MAPKs were previously shown to serve as preferred substrates. The reporter assays demonstrated that the serum-induced enhancement of transcription from serum response element was significantly inhibited by expression of a dominant-negative form of MEK5, which was a direct and specific activator for ERK5 and that transcription from serum response element mediated by the Ets-domain transcription factor Sap1a, but not by Elk1, was stimulated by coexpression of ERK5 and active MEK5. In addition, Sap1a was shown to be phosphorylated by ERK5 in vitro and by the activation of the ERK5 pathway in cells. Moreover, the serum-induced c-Fos expression was markedly inhibited by expression of dominant-negative MEK5. These results reveal a novel signaling pathway to the nucleus mediated by ERK5 that functions downstream of receptor tyrosine kinases to induce immediate early genes, in parallel with the classical MAPK cascade.
Highlights
The nucleotide sequence reported in this paper has been submitted to the DDBJ/GenBankTM/EBI Data Bank with accession numbers AB019373 and AB019374
We have shown that ERK5 is strongly activated by epidermal growth factor (EGF) and nerve growth factor (NGF) through Ras and that the ERK5 pathway is blocked by several inhibitors known as the classical mitogen-activated protein kinase (MAPK) pathway inhibitors
Activation of ERK5 by EGF and NGF—Here we have shown that ERK5 is strongly activated by EGF and NGF whose receptors are tyrosine kinases
Summary
(Received for publication, December 11, 1998, and in revised form, April 28, 1999). Sachiko Kamakura, Tetsuo Moriguchi, and Eisuke Nishida‡ From the Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan. The serum-induced c-Fos expression was markedly inhibited by expression of dominant-negative MEK5 These results reveal a novel signaling pathway to the nucleus mediated by ERK5 that functions downstream of receptor tyrosine kinases to induce immediate early genes, in parallel with the classical MAPK cascade. Two TCF proteins, Elk and Sap1a, which belong to the Ets transcription factor family, are phosphorylated and activated by classical MAPKs, JNK, and p38 [11, 15,16,17,18] It has remained unclear, whether ERK5 functions at the element, serum stimulation was shown to induce ERK5 activation [14]. These findings reveal a novel signaling pathway from the plasma membrane to the nucleus that is mediated by the MEK5-ERK5 pathway
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