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c-Jun phosphorylation by the human vaccinia-related kinase 1 (VRK1) and its cooperation with the N-terminal kinase of c-Jun (JNK)

Abstract

The VRK1 kinase is a novel Ser-Thr kinase in the human kinome that diverged from the casein kinase 1 branch. These kinases phosphorylate transcription factors related to stress responses, such as p53. In this report we have studied the phosphorylation of the transcription factor c-Jun in its N-terminal region. The VRK1 protein phosphorylates c-Jun with a Km of 0.4 μ M, and is not inhibited by SP600125. VRK1 phosphorylates c-Jun in Ser63 and Ser73 in vitro, the same residues targeted by the N-terminal kinase of c-Jun (JNK). This phosphorylation induces the stabilization and accumulation of the c-Jun protein. VRK1 phosphorylates the endogenous c-Jun in Ser63. VRK1 activates c-Jun dependent transcription, which is dependent on phosphorylation of Ser63 and Ser73. The c-Jun with Ser63Ala and Ser73Ala substitutions is not transcriptionally active when cotransfected with VRK1. VRK1 interacts with c-Jun but not with JNK. The cotransfection of VRK1 and JNK has an additive effect on the transcriptional activation of c-Jun indicating that they can cooperate when both are at suboptimal dose; otherwise, maximum effect by one of them prevents the effect of the other. The VRK1-c-Jun connection represents a component of a new signaling pathway whose upstream elements remain to be identified.

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Acknowledgements

AS and CS have predoctoral fellowships from Consejo Superior de Investigaciones Científicas and the Fundação para a Ciência e a Tecnologia (Portugal) respectively. This work was funded by grants from Ministerio de Educación y Ciencia (SAF2000-0169, SAF2004-2900), Fondo de Investigación Sanitaria (FIS02/0585), Junta de Castilla y León-Consejerías de Educación (CSI18-03) and Sanidad (SA 01/02), Fundación de Investigación Médica MMA and Fundación Memoria Samuel Solórzano Barruso.

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Correspondence to Pedro A Lazo.

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Sevilla, A., Santos, C., Barcia, R. et al. c-Jun phosphorylation by the human vaccinia-related kinase 1 (VRK1) and its cooperation with the N-terminal kinase of c-Jun (JNK). Oncogene 23, 8950–8958 (2004). https://doi.org/10.1038/sj.onc.1208015

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