A novel mitogen-activated protein kinase docking site in the N terminus of MEK5alpha organizes the components of the extracellular signal-regulated kinase 5 signaling pathway.
The alternative splicing of the mek5 gene gives rise to two isoforms. MEK5beta lacks an extended N terminus present in MEK5alpha. Comparison of their activities led us to identify a novel mitogen-activated protein kinase (MAPK) docking site in the N terminus of MEK5alpha that is distinct from the consensus motif identified in the other MAPK kinases. It consists of a cluster of acidic residues at position 61 and positions 63 to 66. The formation of the MEK5/extracellular signal-regulated kinase 5 (ERK5) complex is critical for MEK5 to activate ERK5, to increase transcription via MEF2, and to enhance cellular survival in response to osmotic stress. Certain mutations in the ERK5 docking site that prevent MEK5/ERK5 interaction also abrogate the ability of MEKK2 to bind and activate MEK5. However, the identification of MEK5alpha mutants with selective binding defect demonstrates that the MEK5/ERK5 interaction does not rely on the binding of MEK5alpha to MEKK2 via their respective PB1 domains. Altogether these results establish that the N terminus of MEK5alpha is critical for the specific organization of the components of the ERK5 signaling pathway.
Seyfried
Jan
J
Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom.
Wang
Xin
X
Kharebava
Giorgi
G
Tournier
Cathy
C
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002470:Cell Survival; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D000939:Epitopes / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D026161:MADS Domain Proteins / Q000378:metabolism; D048671:MAP Kinase Kinase 5 / Q000737:chemistry* / Q000378:metabolism; D048748:MAP Kinase Kinase Kinase 3 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D064326:MEF2 Transcription Factors; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
D000939:Epitopes; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D018006:Myogenic Regulatory Factors; D020033:Protein Isoforms; D008156:Luciferases; D005982:Glutathione Transferase; D048054:Mitogen-Activated Protein Kinase 7; D048748:MAP Kinase Kinase Kinase 3; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human