Negative regulation of ERK activity by VRK3-mediated activation of VHR phosphatase.
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 plasticity. Mitogen-activated protein kinase phosphatases (MKPs) selectively inactivate ERKs by dephosphorylating critical phosphothreonine and phosphotyrosine residues. Transcriptional induction of MKP expression and posttranscriptional stabilization of MKP mRNA are well-documented as negative-feedback mechanisms for ERK signalling. Vaccinia-related kinase 3 (VRK3) is a member of the novel VRK family, 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), which specifically dephosphorylates and inactivates ERK in the nucleus. 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.
Kang
Tae-Hong
TH
Department of Life Science, Biotechnology Research Center, Division of Molecular and Life Science, Pohang University of Science and Technology (POSTECH), San-31, Hyoja-Dong, Pohang, 790-784, Republic of Korea.
Kim
Kyong-Tai
KT
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D015151:Immunoblotting; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D016716:PC12 Cells; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
D020932:Nerve Growth Factor; D017346:Protein Serine-Threonine Kinases; C475142:Vrk3 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D013755:Tetradecanoylphorbol Acetate