Serine/Threonine Kinase Mirk/Dyrk1B Is an Inhibitor of Epithelial Cell Migration and Is Negatively Regulated by the Met Adaptor Ran-binding Protein M

Zou, Yufei; Lim, Seunghwan; Lee, Kangmoon; Deng, Xiaobing; Friedman, Eileen

doi:10.1074/jbc.m307556200

Cited by 67 publications

(75 citation statements)

References 42 publications

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“…Mv1Lu cells growth arrest in G 0 /G 1 in response to transforming growth factor-␤1 or to culture in serum-free conditions, whereas treatment with a cellular mitogen releases this arrest (15). In addition, we recently have made a stable Mirk-inducible subline from Mv1Lu cells and have shown that the induction of Mirk inhibited the migration of these cells in wounding experiments and inhibited their invasion through polycarbonate Transwell filters (12). Therefore, we know that Mirk exhibits biological activity in these epithelial cells.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, transient overexpression of Mirk in epithelial cells blocked cells in G 0 /G 1 . In earlier studies, we had made a stable Mirk-inducible subline from nontransformed Mv1Lu lung epithelial cells (12). The induction of Mirk caused a 30 -40% inhibition of Mv1Lu cell entry into S phase as measured by decreased uptake of [ 3 H]thymidine (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The Mirkinducible Mv1Lu C9 subline was isolated by stably transfecting cells with a pCMVLac1-repressor construct, selecting the hygromycin-resistant clone, and then stably transfecting Mirk in a pOPRSV1/MCS vector using G418 (LacSwitch II System, Stratagene) (12).…”

Section: Methodsmentioning

confidence: 99%

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Mirk/dyrk1B Kinase Destabilizes Cyclin D1 by Phosphorylation at Threonine 288

Zou

Ewton

Deng

et al. 2004

Journal of Biological Chemistry

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110

128

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The phosphorylation of cyclin D1 at threonine 286 by glycogen synthase kinase 3␤ (GSK3␤) 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 Cell cycle progression in eukaryotic cells is mediated by cyclin-dependent kinases (CDKs). 1 The D-type cyclins, D1, D2, and D3, increase in nuclear abundance in G 1 in response to mitogens, facilitate the import of CDK4 into the nucleus (1), and assemble combinatorially with CDK4 or CDK6 into complexes that phosphorylate the retinoblastoma protein, releasing factors needed for the progression into S phase. Cyclin D1 is translocated into the cytoplasm during S phase where it is destroyed by the proteasome following phosphorylation at threonine 286 by GSK3␤ (2, 3). Mutant cyclin D1-T286A, which cannot be phosphorylated by GSK3␤, is stabilized in the nucleus and is capable of transforming murine fibroblasts, whereas overexpression of wild-type cyclin D1 cannot act alone to transform such cells (4). A cyclin D1 isoform derived by alternative splicing was shown to lack threonine 286, enabling this cyclin D1 isoform to remain nuclear throughout the cell cycle, remain highly expressed, and function to facilitate transformation of NIH3T3 cells (5). This cyclin D1 splice variant was also found in tumor-derived cells and primary human esophageal tumors (5). Overexpression of cyclin D1 occurs in several cancers including breast, pancreatic, and esophageal (6), suggesting that either increased transcription, transcription of stable splice variants, or dysregulation of cyclin D1 turnover may frequently occur in cancer.In this study, we have studied the interaction of the ubiquitously expressed protein kinase Mirk/dyrk1B with cyclin D1. Mirk/dyrk1B is an arginine-directed serine/threonine kinase (7), which functions as a transcriptional co-activator and is activated through the stress-activated mitogen-activated protein kinase kinase MKK3 (8). We have shown recently that Mirk stabilizes the CDK inhibitor p27kip1 in the G 0 phase of the cell cycle in NIH3T3 fibroblasts, whereas depletion of Mirk by RNA interference increases cell cycling as measured by increased PCNA expression (9). Mirk expression is decreased by mitogen activation of the MEK-ERK pathway during G 1 (10), restricting Mirk function primarily to G 0 and early G 1 . We now confirm that transient overexpression of Mirk in nontransformed Mv1Lu lung epithelial cells increases the length of G 0 /G 1 by FACS analysis and that Mirk targets the G 1 cell cycle regulator, cyclin D1, t...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Mirk/dyrk1B Kinase Destabilizes Cyclin D1 by Phosphorylation at Threonine 288

Zou

Ewton

Deng

et al. 2004

Journal of Biological Chemistry

Self Cite

110

128

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“…Jab1 functions as an adaptor between CRM1 and p27 (23). The Mirk-containing nuclear complexes have not been completely characterized, but we found in an earlier study that they do not contain Jab1 (22), which is found within the 450-kDa signalosome and smaller complexes (22,23).…”

mentioning

confidence: 91%

“…Possibly Mirk and p27 occupy a different part of the nucleus than CRM1 during G 0 . Mirk is found in 670-kDa complexes within the nucleus together with the Ran-binding protein RanBPM (12,22). Jab1 functions as an adaptor between CRM1 and p27 (23).…”

mentioning

confidence: 99%

The Cyclin-dependent Kinase Inhibitor p27Kip1 Is Stabilized in G0 by Mirk/dyrk1B Kinase

Deng

Mercer

Shah

et al. 2004

Journal of Biological Chemistry

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125

156

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RanBPM regulates the progression of neuronal precursors through M‐phase at the surface of the neocortical ventricular zone

Chang

Paramasivam

Girgenti

et al. 2009

Developmental Neurobiology

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Many of the mitoses that produce pyramidal neurons in neocortex occur at the dorsolateral surface of the lateral ventricles in the embryo. RanBPM was found in a yeast two-hybrid screen to potentially interact with citron kinase (CITK), a protein shown previously to localize to the surface of the lateral ventricles and to be essential to neurogenic mitoses. Similar to its localization in epithelia, RanBPM protein is concentrated at the adherens junctions in developing neocortex. The biochemical interaction between CITK and RanBPM was confirmed in co-immunoprecipitation and protein overlay experiments. To test for a functional role of RanPBM in vivo, we used in utero RNAi. RanBPM RNAi decreased the polarization of CITK to the ventricular surface, increased the number of cells in mitosis and decreased the number of cells in cytokinesis. Finally, the effect of RanBPM knockdown on mitosis was reversed in embryos mutant for CITK. Together, these results indicate that RanBPM, potentially through interaction with CITK, plays a role in the progression of neocortical precursors through M-phase at the ventricular surface.

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Serine/Threonine Kinase Mirk/Dyrk1B Is an Inhibitor of Epithelial Cell Migration and Is Negatively Regulated by the Met Adaptor Ran-binding Protein M

Abstract: Minibrain-related kinase (Mirk)/Dyrk1B is an arginine-directed serine/threonine kinase that is active in skeletal muscle development but is also expressed in various carcinomas. In the current study, the Met adaptor protein Ran-binding protein M (

Cited by 67 publications

References 42 publications

Mirk/dyrk1B Kinase Destabilizes Cyclin D1 by Phosphorylation at Threonine 288

Mirk/dyrk1B Kinase Destabilizes Cyclin D1 by Phosphorylation at Threonine 288

The Cyclin-dependent Kinase Inhibitor p27Kip1 Is Stabilized in G0 by Mirk/dyrk1B Kinase

RanBPM regulates the progression of neuronal precursors through M‐phase at the surface of the neocortical ventricular zone

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