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Mol. Cell. Biol. doi:10.1128/MCB.00025-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Vaccinia-related kinase 2 (VRK2) modulates the stress response to hypoxia mediated by TAK1

Programa de Oncología Translacional, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, E-37007, Spain

^* To whom correspondence should be addressed. Email: plazozbi{at}usal.es.

	Abstract

Hypoxia represents a major stress that requires an immediate cellular response in which participate different signaling pathways. Hypoxia induces an increase in the activity of TAK1, an atypical MAPKKK, which responds to oxidative stress by triggering cascades leading to the activation of c-Jun N-terminal kinase (JNK). JNK activation by hypoxia requires the assembly with the JIP1 scaffold protein, which might also interact with other intracellular proteins that are less well known but that might modulate MAPK signaling. We report that TAK1 is able to form a stable complex with JIP1 and thus regulate the activation of JNK, which in turn determines the cellular stress response to hypoxia. This activation of TAK1-JIP1-JNK is suppressed by vaccinia-related kinase 2 (VRK2). VRK2A is able to interact with TAK1 by its C-terminal region forming stable complexes. The kinase activity of VRK2 is not necessary for this interaction or downregulation of AP1-dependent transcription. Furthermore, reduction of endogenous VRK2 level with shRNA can increase the response induced by hypoxia, suggesting that the intracellular levels of VRK2 can determine the magnitude of this stress response.