p38alpha isoform Mxi2 binds to extracellular signal-regulated kinase 1 and 2 mitogen-activated protein kinase and regulates its nuclear activity by sustaining its phosphorylation levels.
Mxi2 is a p38alpha splice isoform that is distinctively activated by mitogenic stimuli. Here we show that Mxi2 immunoprecipitates carry a kinase activity that is persistently activated by epidermal growth factor in a fashion regulated by Ras, Raf, and MEK. We demonstrate that this kinase activity can be attributed not to Mxi2 but rather to extracellular signal-regulated kinases 1 and 2 (ERK1/2), which coimmunoprecipitated with Mxi2 both by ectopic expression and in a physiological environment like the kidney. Furthermore, we provide evidence that Mxi2-ERK interaction has profound effects on ERK function, demonstrating that Mxi2 prolongs the duration of the ERK signal by sustaining its phosphorylation levels. Interestingly, we show that the effects of Mxi2 on ERK are restricted to nuclear events. Mxi2 potently up-regulates ERK-mediated activation of the transcription factors Elk1 and HIF1alpha but has no effect on the activity of ERK cytoplasmic substrates RSK2 and cPLA(2), induced by epidermal growth factor or by MEK. Overall, our findings point to Mxi2 as a unique member of the p38 family that may have an unprecedented role in the regulation of the functions of ERK mitogen-activated protein kinases.
Sanz-Moreno
Victoria
V
Departamento de Biología Molecular, Universidad de Cantabria, Santander 39011, Spain.
Casar
Berta
B
Crespo
Piero
P
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D048369:MAP Kinase Kinase 1; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D007527:Isoenzymes; D010446:Peptide Fragments; D004815:Epidermal Growth Factor; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins