Mirk/dyrk1B kinase destabilizes cyclin D1 by phosphorylation at threonine 288
Zou, Y; Ewton, DZ; Deng, X; Mercer, SE; Friedman, E
HERO ID
1617154
Reference Type
Journal Article
Year
2004
Language
English
PMID
| HERO ID | 1617154 |
|---|---|
| In Press | No |
| Year | 2004 |
| Title | Mirk/dyrk1B kinase destabilizes cyclin D1 by phosphorylation at threonine 288 |
| Authors | Zou, Y; Ewton, DZ; Deng, X; Mercer, SE; Friedman, E |
| Journal | Journal of Biological Chemistry |
| Volume | 279 |
| Issue | 26 |
| Page Numbers | 27790-27798 |
| Abstract | The phosphorylation of cyclin D1 at threonine 286 by glycogen synthase kinase 3beta (GSK3beta) 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 G(0)/G(1)-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 G(0)/G(1). 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 GSK3beta. Mirk-phosphorylated cyclin D1 mutated at the GSK3beta phosphorylation site and was capable of phosphorylating cyclin D1 in the presence of the GSK3beta inhibitor LiCl. Mirk may function together with GSK3beta to assist cell arrest in G(0)/G(1) by destabilizing cyclin D1. |
| Doi | 10.1074/jbc.M403042200 |
| Pmid | 15075324 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |