Abstract
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.
Highlights
The mitogen-activated protein kinase (MAPK) signaling pathways regulate numerous physiological processes during development and pathogenesis [10]
A conserved cluster of two to five basic residues identified in the N terminus of MEK1 and -2 and MKK3, -4, -6, and -7 constitutes a consensus MAPK binding site that is necessary for the transmission of the signal [1, 28]
We have recently provided genetic evidence that MEK5 is a nonredundant component of the extracellular signal-regulated kinase 5 (ERK5)/myocyte enhancer factor 2 (MEF2)-dependent cell survival pathway [29]
Summary
The mitogen-activated protein kinase (MAPK) signaling pathways regulate numerous physiological processes during development and pathogenesis [10]. The N-terminal extension of MEK5␣ has been implicated in its restricted localization to the particulate fraction, while MEK5 is ubiquitously distributed and is primarily cytosolic [7] It contains a phox and Bem1p (PB1) domain that mediates the binding interaction of MEK5␣ with the MEK kinases, MEKK2 and MEKK3 [17]. Consistent with this study, MEK5 that lacks the PB1 domain has been identified as a kinase-dead dominant-negative variant that can suppress ERK5 signaling [4] This is disputed by the ability of a MEK5 transgene to activate ERK5 in vivo and to promote eccentric cardiac hypertrophy that progresses to dilated cardiomyopathy and sudden death [18]. Further studies demonstrate that the docking of ERK5 to MEK5 is essential for the function of MEK5 as a cell survival factor
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