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Molecular and Cellular Biology, May 2003, p. 3079-3090, Vol. 23, No. 9
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.9.3079-3090.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

p38{alpha} 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

Victoria Sanz-Moreno, Berta Casar, and Piero Crespo*

Departamento de Biología Molecular, Universidad de Cantabria, Santander 39011, and Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Madrid 28029, Spain

Received 6 September 2002/ Returned for modification 25 October 2002/ Accepted 27 January 2003

Mxi2 is a p38{alpha} 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 HIF1{alpha} but has no effect on the activity of ERK cytoplasmic substrates RSK2 and cPLA2, 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.

* Corresponding author. Mailing address: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Arturo Duperier 4, Madrid 28029, Spain. Phone: 34-91-5854886. Fax: 34-91-5854587. E-mail: pcrespo{at}iib.uam.es.

Molecular and Cellular Biology, May 2003, p. 3079-3090, Vol. 23, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.9.3079-3090.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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