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Negative regulation of ERK activity by VRK3-mediated activation of VHR phosphatase

Nature Cell Biology volume 8, pages 863–869 (2006)Cite this article

Abstract

Extracellular signal regulated kinases (ERKs) represent a signalling hub in many physiological responses and have pivotal functions in cell proliferation, differentiation, development and death, as well as in synaptic plasticity1,2. Mitogen-activated protein kinase phosphatases (MKPs) selectively inactivate ERKs by dephosphorylating critical phosphothreonine and phosphotyrosine residues3,4. Transcriptional induction of MKP expression5,6 and posttranscriptional stabilization of MKP mRNA7 are well-documented as negative-feedback mechanisms for ERK signalling. Vaccinia-related kinase 3 (VRK3) is a member of the novel VRK family8,9, but its function has not been defined. Here, we show that VRK3 suppresses ERK activity through direct binding to one of the MKPs, vaccinia H1-related (VHR)10, which specifically dephosphorylates and inactivates ERK in the nucleus11. Notably, VRK3 enhances the phosphatase activity of VHR by a mechanism independent of its kinase activity. VRK3 is therefore a member of a new class of phosphatase-activating kinases that regulate the activity of ERK. Our findings show that direct interaction of VHR with VRK3 posttranslationally regulates ERK signalling.

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Figure 1: VRK3 suppresses phosphorylation of ERK.
Figure 2: Requirement for VHR in the VRK3-mediated inactivation of ERK.
Figure 3: VRK3 enhances the VHR activity by direct interaction.
Figure 4: ERK activation induces VRK3 expression.
Figure 5: Regulation of NGF-induced neurite outgrowth by VRK3 in PC12 cells.

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Acknowledgements

We wish to thank to K.J. Kim (X-ray research group, POSTECH, Pohang, Korea) for purification of recombinant proteins, Y.C. Sung (POSTECH) for recombinant defective Sindbis virus, H.S. Yoon (Nangyang Technological University, Singapore) for recombinant phosphorylated-ERK2 protein and E.M. Hur (POSTECH) for critical discussion. This study was supported by a grant from the National R&D Program for Cancer Control (0520250-1), the Ministry of Health & Welfare and Brain Korea 21 programme of the Ministry of Education, Republic of Korea.

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  1. Department of Life Science, Division of Molecular and Life Science, Biotechnology Research Center, Pohang University of Science and Technology (POSTECH), San-31, Hyoja-Dong, 790-784, Pohang, Republic of Korea

    Tae-Hong Kang & Kyong-Tai Kim

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Correspondence to Kyong-Tai Kim.

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Kang, TH., Kim, KT. Negative regulation of ERK activity by VRK3-mediated activation of VHR phosphatase. Nat Cell Biol 8, 863–869 (2006). https://doi.org/10.1038/ncb1447

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