PMID- 11160424 OWN - NLM STAT- MEDLINE DCOM- 20010405 LR - 20220309 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 21 IP - 2 DP - 2001 Jan 15 TI - Differential regulation of mitogen-activated protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons. PG - 434-43 AB - Activation of the extracellular signal-regulated kinase 1 (ERK1) and ERK2 by neurotrophins, neuronal activity, or cAMP has been strongly implicated in differentiation, survival, and adaptive responses of neurons during development and in the adult brain. Recently, a new member of the mitogen-activated protein (MAP) kinase family, ERK5, was discovered. Like ERK1 and ERK2, ERK5 is expressed in neurons, and ERK5 stimulation by epidermal growth factor is blocked by the MAP kinase/ERK kinase 1 (MEK1) inhibitors PD98059 and U0126. This suggests the interesting possibility that some of the functions attributed to ERK1/2 may be mediated by ERK5. However, the regulatory properties of ERK5 in primary cultured neurons have not been reported. Here we examined the regulation of ERK5 signaling in primary cultured cortical neurons. Our data demonstrate that, similar to ERK1/2, ERK5 is activated by neurotrophins including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4. BDNF stimulation of ERK5 required the activity of MEK5. Surprisingly, ERK5 was not stimulated by cAMP or neuronal activity induced by glutamate or membrane depolarization. In contrast to ERK1/2, ERK5 strongly activated the transcriptional activity of myocyte enhancer factor 2C (MEF2C) in pheochromocytoma 12 (PC12) cells and was required for neurotrophin stimulation of MEF2C transcription in both PC12 cells and cortical neurons. Furthermore, ERK1/2, but not ERK5, induced transcription from Elk1 and the cAMP/ Ca(2+) response element in PC12 cells. Our data suggest that mechanisms for regulation of ERK5 and downstream transcriptional pathways regulated by ERK5 are distinct from those of ERK1/2 in neurons. Furthermore, ERK5 is the first MAP kinase identified whose activity is stimulated by neurotrophins but not by neuronal activity. FAU - Cavanaugh, J E AU - Cavanaugh JE AD - Departments of Environmental Health and Pharmacology, University of Washington, Seattle, Washington 98195-7234, USA. FAU - Ham, J AU - Ham J FAU - Hetman, M AU - Hetman M FAU - Poser, S AU - Poser S FAU - Yan, C AU - Yan C FAU - Xia, Z AU - Xia Z LA - eng GR - T32 AG000057/AG/NIA NIH HHS/United States GR - NS37359/NS/NINDS NIH HHS/United States GR - 2 T32 AG00057-21/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Enzyme Inhibitors) RN - 0 (MEF2 Transcription Factors) RN - 0 (Myogenic Regulatory Factors) RN - 0 (Nerve Growth Factors) RN - 3KX376GY7L (Glutamic Acid) RN - 660YQ98I10 (Potassium Chloride) RN - E0399OZS9N (Cyclic AMP) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 7) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 2.7.12.2 (MAP Kinase Kinase 5) RN - EC 2.7.12.2 (Map2k5 protein, rat) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism/pharmacology MH - Cells, Cultured MH - Cerebral Cortex/cytology/metabolism MH - Cyclic AMP/*metabolism/pharmacology MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Enzyme Inhibitors/pharmacology MH - Genes, Reporter MH - Glutamic Acid/metabolism/pharmacology MH - MAP Kinase Kinase 5 MH - MEF2 Transcription Factors MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3 MH - Mitogen-Activated Protein Kinase 7 MH - Mitogen-Activated Protein Kinase Kinases/genetics/metabolism MH - Mitogen-Activated Protein Kinases/antagonists & inhibitors/genetics/*metabolism MH - Myogenic Regulatory Factors/biosynthesis MH - Nerve Growth Factors/*metabolism MH - Neurons/cytology/*metabolism MH - PC12 Cells MH - Phosphorylation MH - Potassium Chloride/metabolism/pharmacology MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction/drug effects/*physiology PMC - PMC6763829 EDAT- 2001/02/13 11:00 MHDA- 2001/04/06 10:01 PMCR- 2001/07/15 CRDT- 2001/02/13 11:00 PHST- 2001/02/13 11:00 [pubmed] PHST- 2001/04/06 10:01 [medline] PHST- 2001/02/13 11:00 [entrez] PHST- 2001/07/15 00:00 [pmc-release] AID - 21/2/434 [pii] AID - 4913 [pii] AID - 10.1523/JNEUROSCI.21-02-00434.2001 [doi] PST - ppublish SO - J Neurosci. 2001 Jan 15;21(2):434-43. doi: 10.1523/JNEUROSCI.21-02-00434.2001.