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.