Mirk/dyrk1B Kinase Destabilizes Cyclin D1 by Phosphorylation at Threonine 288
Open Access
- 1 June 2004
- journal article
- Published by Elsevier BV in Journal of Biological Chemistry
- Vol. 279 (26), 27790-27798
- https://doi.org/10.1074/jbc.m403042200
Abstract
The phosphorylation of cyclin D1 at threonine 286 by glycogen synthase kinase 3β (GSK3β) has been shown to be required for the ubiquitination and nuclear export of cyclin D1 and its subsequent degradation in the proteasome. The mutation of the nearby residue, threonine 288, to nonphosphorylatable alanine has also been shown to reduce the ubiquitination of cyclin D1, suggesting that phosphorylation at threonine 288 may also lead to degradation of cyclin D1. We now demonstrate that the G0/G1-active arginine-directed protein kinase Mirk/dyrk1B binds to cyclin D1 and phosphorylates cyclin D1 at threonine 288 in vivo and that the cyclin D1-T288A construct is more stable than wild-type cyclin D1. Transient overexpression of Mirk in nontransformed Mv1Lu lung epithelial cells blocked cells in G0/G1. Depletion of endogenous Mirk by RNA interference increased cyclin D1 protein levels but not mRNA levels, indicating that Mirk destabilizes cyclin D1 protein. Destabilization was confirmed by induction of a stable Mirk transfectant of Mv1Lu cells, which blocked cell migration (Zou, Y., Lim, S., Lee, K., Deng, X., and Friedman, E. (2003) J. Biol. Chem. 278, 49573-49581), and caused a decrease in the half-life of endogenous cyclin D1, concomitant with an increase in Mirk expression. In vitro cyclin D1 was phosphorylated in an additive fashion by Mirk and GSK3β. Mirk-phosphorylated cyclin D1 mutated at the GSK3β phosphorylation site and was capable of phosphorylating cyclin D1 in the presence of the GSK3β inhibitor LiCl. Mirk may function together with GSK3β to assist cell arrest in G0/G1 by destabilizing cyclin D1.Keywords
This publication has 26 references indexed in Scilit:
- Phosphorylation of Ser640 in Muscle Glycogen Synthase by DYRK Family Protein KinasesPublished by Elsevier BV ,2004
- Mirk/dyrk1B Is a Rho-induced Kinase Active in Skeletal Muscle DifferentiationJournal of Biological Chemistry, 2003
- Rapid turnover of cell‐cycle regulators found in Mirk/dyrk1B transfectantsInternational Journal of Cancer, 2002
- Regulation of Gli1 Transcriptional Activity in the Nucleus by Dyrk1Journal of Biological Chemistry, 2002
- The Stress-activated Protein Kinases p38α and JNK1 Stabilize p21Cip1 by PhosphorylationPublished by Elsevier BV ,2002
- Mirk Protein Kinase Is Activated by MKK3 and Functions as a Transcriptional Activator of HNF1αPublished by Elsevier BV ,2002
- Efficient eukaryotic expression system for authentic human sex hormone-binding globulinBiochemical Journal, 2001
- Protein Kinase Dyrk1 Activates cAMP Response Element-binding Protein during Neuronal Differentiation in Hippocampal Progenitor CellsJournal of Biological Chemistry, 2001
- Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway.Genes & Development, 1997
- Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase BNature, 1995