Abstract
Minibrain-related kinase (Mirk)/dual-specificity tyrosine-regulated kinase (Dyrk)1B is one of the best functionally characterized members of the Dyrk/Minibrain family of dual-specificity kinases. Dyrk family kinases are highly conserved mediators of growth control and differentiation. Mirk is expressed at high levels in skeletal muscle; thus, most of the recent studies of Mirk have used myogenesis as a model system to explore the function of Mirk in a native physiological environment. These studies have revealed that Mirk is a multifunctional Ser/Thr kinase that plays a critical role in muscle differentiation by regulatory effects on motility, transcription, cell cycle progression, and cell survival. Mirk also is found at elevated levels in various solid tumors, where it seems to act as a tumor survival factor. This review summarizes the known regulators and functions of Mirk kinase and outlines opportunities for future studies of Mirk in the fields of muscle and tumor biology.
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Becker, W., Weber, Y., Wetzel, K., Eirmbter, K., Tejedor, F., and Joost, H.-G. (1998) Sequence characteristics, subcellular localization and substrate specificity of Dyrk-related kinases, a novel family of dual specificity protein kinases. J Biol Chem. 273, 25,893–25,902.
Lee, K. and Friedman, E. (1998) Novel dual-specific tyrthr/ser kinase cloned from colon carcinoma cells. Proc AACR. 39, 273.
Lee, K., Deng, X., and Friedman, E. (2000) Mirk protein kinase is a mitogen-activated protein kinase substrate that mediates survival of colon cancer cells. Cancer Res. 60, 3631–3637.
Leder, S., Weber, Y., Altafai, X., Estivill, X., Joost, H. G., and Becker, W. (1999) Cloning and characterization of DYRK1B, a novel member of the DYRK family of protein kinases. Biochem. Biophys. Res. Commun. 254, 474–479.
Kentrup, H., Becker, W., Heukelbach, J., et al. (1996) Dyrk, a dual specificity protein kinase with unique structural features whose activity is dependent on tyrosine residues between subdomains VII and VIII. J. Biol. Chem. 271, 3488–3495.
Becker, W. and Joost, H. G. (1999) Structural and functional characteristics of Dyrk, a novel subfamily of protein kinases with dual specificity. Prog. Nucleic Acids Res. Mol. Biol. 62, 1–17.
Manning, G., Whyte, D. B., Martinez, R., Hunter, T., and Sudarsanam, S. (2002) The protein kinase complement of the human genome. Science 298, 1912–1934.
Jope, R. S. and Johnson, G. V. (2004) The glamour and gloom of glycogen synthase kinase-3. Trends Biochem. Sci. 29, 95–102.
Muraki, M., Ohkawara, B., Hosoya, T., et al. (2004) Manipulation of alternative splicing by a newly developed inhibitor of Clks. J. Biol. Chem. 279, 24,246–24,254.
Duncan, P. I., Stojdl, D. F., Marius, R. M., and Bell, J. C. (1997) In vivo regulation of alternative pre-mRNA splicing by the Clk1 protein kinase. Mol. Cell. Biol. 17, 5996–6001.
Myers, M. P., Murphy, M. B., and Landreth, G. (1994) The dual-specificity CLK kinase induces neuronal differentiation of PC12 cells. Mol. Cell. Biol. 14, 6954–6961.
Kannan, N. and Neuwald, A. F. (2004) Evolutionary constraints associated with functional specificity of the CMGC protein kinases MAPK, CDK, GSK, SRPK, DYRK, and CK2alpha. Protein Sci. 13, 2059–2077.
Kuroyanagi, N., Onogi, H., Wakabayashi, T., and Hagiwara, M. (1998) Novel SR-protein-specific kinase, SRPK2, disassembles nuclear speckles. Biochem. Biophys. Res. Commun. 242, 357–364.
Wang, A., Forman-Kay, J., Luo, Y., et al. (1997) Identification and characterization of human genes encoding Hprp3p and Hprp4p, interacting components of the spliceosome. Hum. Mol. Genet. 6, 2117–2126.
Gross, T., Lutzelberger, M., Weigmann, H., Klingenhoff, A., Shenoy, S., and Kaufer, N. F. (1997) Functional analysis of the fission yeast Prp4 protein kinase involved in pre-mRNA splicing and isolation of a putative mammalian homologue. Nucleic Acids Res. 25, 1028–1035.
Wang, H. Y., Lin, W., Dyck, J. A., et al. (1998) SRPK2: a differentially expressed SR protein-specific kinase involved in mediating the interaction and localization of pre-mRNA splicing factors in mammalian cells. J. Cell Biol. 140, 737–750.
Kim, Y. H., Choi, C. Y., Lee, S. J., Conti, M. A., and Kim, Y. (1998) Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors. J. Biol. Chem. 273, 25,875–25,879.
Guimera, J., Casas, C., Estivill, X., and Pritchard, M. (1999) Human minibrain homologue (MNBH/DYRK1): characterization, alternative splicing, differential tissue expression and overexpression in Down syndrome. Genomics 57, 407–418.
Tejedor, F., Zhu, X. R., Kaltenbach, E., et al. (1995) Minibrain: a new protein kinase family involved in postembryonic neurogenesis in Drosophila. Neuron 14, 287–301.
Galceran, J., de Graaf, K., Tejedor, F. J., and Becker, W. (2003) The MNB/DYRK1A protein kinase: genetic and biochemical properties. J. Neural Transm. Suppl. 67, 139–148.
Hammerle, B., Elizalde, C., Galceran, J., Becker, W., and Tejedor, F. J. (2003) The MNB/DYRK1A protein kinase: neurobiological functions and Down syndrome implications. J. Neural. Transm. Suppl. 67, 129–137.
Altafaj, X., Dierssen, M., Baamonde, C., et al. (2001) Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome. Hum. Mol. Genet. 10, 1915–1923.
Fotaki, V., Dierssen, M., Alcantara, S., et al. (2002) Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice. Mol. Cell Biol. 22, 6636–6647.
Fotaki, V., Martinez De Lagran, M., Estivill, X., Arbones, M., and Dierssen, M. (2004) Haploinsufficiency of Dyrk1A in mice leads to specific alterations in the development and regulation of motor activity. Behav. Neurosci. 118, 815–821.
Yang, E., Ahn, Y. S., and Chung, K. (2001) Protein kinase Dyrk1 activates cAMP response element-binding protein during neuronal differentiation in hippocampal progenitor cells. J. Biol. Chem. 276, 39,819–39,824.
Wiechmann, S., Czajkowska, H., de Graaf, K., Grotzinger, J., Joost, H. G., and Becker, W. (2003) Unusual function of the activation loop in the protein kinase DYRK1A. Biochem. Biophys. Res. Commun. 302, 403–408.
Matsuo, R., Ochiai, W., Nakashima, K., and Taga, T. (2001) A new expression cloning strategy for isolation of substrate-specific kinases by using phosphorylation site-specific antibody. J. Immunol. Methods 247, 141–151.
Mao, J., Maye, P., Kogerman, P., et al. (2002) Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1. J. Biol. Chem. 277, 35,156–35,161.
von Groote-Bidlingmaier, F., Schmoll, D., Orth, H. M., Joost, H. G., Becker, W., and Barthel, A. (2003) DYRK1 is a co-activator of FKHR (FOXO1a)-dependent glucose-6-phosphatase gene expression. Biochem. Biophys. Res. Commun. 300, 764–769.
Woods, Y. L., Rena, G., Morrice, N., et al. (2001) The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. Biochem. J. 355, 597–607.
Woods, Y. L., Cohen, P., Becker, W., et al. (2001) The kinase DYRK phosphorylates protein-synthesis initiation factor elF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochem. J. 355, 609–615.
Chen-Hwang, M. C., Chen, H. R., Elzinga, M., and Hwang, Y. W. (2002) Dynamin is a minibrain kinase/dual specificity Yak1-related kinase 1A substrate. J. Biol. Chem. 277, 17,597–17,604.
de Graaf, K., Hekerman, P., Spelten, O., et al. (2004) Characterization of cyclin L2, a novel cyclin with an arginine/serine-rich domain: phosphorylation by DYRK1A and colocalization with splicing factors. J. Biol. Chem. 279, 4612–4624.
Miller, C. T., Aggarwal, S., Lin, T. K., et al. (2003) Amplification and overexpression of the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 2 (DYRK2) gene in esophageal and lung adenocarcinomas. Cancer Res. 63, 4136–4143.
Geiger, J. N., Knudsen, G. T., Panek, L., et al. (2001) mDYRK3 kinase is expressed selectively in late erythroid progenitor cells and attenuates colony-forming unit-erythroid development. Blood 97, 901–910.
Zhang, D., Li, K., Erickson-Miller, C. L., Weiss, M., and Wojchowski, D. M. (2005) DYRK gene structure and erythroid-restricted features of DYRK3 gene expression. Genomics 85, 117–130.
Lord, K. A., Creasy, C. L., King, A. G., et al. (2000) REDK, a novel human regulatory erythyroid kinase. Blood 95, 2838–2846.
Li, K., Zhao, S., Karur, V., and Wojchowski, D. M. (2002) DYRK3 activation, engagement of protein kinase A/cAMP response element-binding protein, and modulation of progenitor cell survival. J. Biol. Chem. 277, 47,052–47,060.
Mercer, S. E., Ewton, D. Z., Deng, X., Lim, S., Mazur, T. R., and Friedman, E. (2005) Mirk/Dyrk1B mediates survival during the differentiation of C2C12 myoblasts. J. Biol. Chem. 280, 25,788–25,801.
Mackeigan, J. P., Murphy, L. O., and Blenis, J. (2005) Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance. Nat. Cell Biol. 7, 591–600.
Leypoldt, F., Lewerenz, J., and Methner, A. (2001) Identification of genes up-regulated by retinoic-acid-induced differentiation of the human neuronal precursor cell line NTERA-2 clD1. J. Neurochem. 76, 806–814.
Lochhead, P. A., Sibbet, G., Kinstrie, R., Cleghon, T., Rylatt, M., Morrison, D. K., and Cleghon, V. (2003) dDYRK2: a novel dual-specificity tyrosine-phosphorylation-regulated kinase in Drosophila. Biochem. J. 374, 381–391.
Raich, W. B., Moorman, C., Lacefield, C. O., et al. (2003) Characterization of Caenorhabditis elegans homologs of the Down syndrome candidate gene DYRK1A. Genetics 163, 571–580.
Pang, K. M., Ishidate, T., Nakamura, K., et al. (2004) The minibrain kinase homolog, mbk-2, is required for spindle positioning and asymmetric cell division in early C. elegans embryos. Dev. Biol. 265, 127–139.
Kassis, S., Melhuish, T., Annan, R. S., et al. (2000) Saccharomyces cerevisiae Yak1p protein kinase autophosphorylates on tyrosine residues and phosphorylates myelin basic protein on a C-terminal serine residue. Biochem. J. 348, 263–272.
Moriya, H., Shimizu-Yoshida, Y., Omori, A., Iwashita, S., Katoh, M., and Sakai, A. (2001) Yak1p, a DYRK family kinase, translocates to the nucleus and phosphorylates yeast Pop2p in response to a glucose signal. Genes Dev. 150, 1217–1228.
Bahler, J. and Pringle, J. R. (1998) Pomlp, a fission yeast protein kinase that provides positional information for both polarized growth and cytokinesis. Genes Dev. 12, 1356–1370.
Taminato, A., Bagattini, R., Gorjao, R., Chen, G., Kuspa, A., and Souza, G. M. (2002) Role for YakA, cAMP, and protein kinase A in regulation of stress responses of Dictyostelium discoideum. Mol. Biol. Cell. 13, 2266–2275.
Garrett, S. and Broach, J. (1989) Loss of Ras activity in Saccharomyces cerevisiae is suppressed by disruptions of a new kinase gene, YAKI, whose product may act downstream of the cAMP-dependent protein kinase. Genes Dev. 3, 1336–1348.
Garrett, S., Menold, M. M., and Broach, J. R. (1991) The Saccharomyces cerevisiae YAK1 gene encodes a protein kinase that is induced by arrest early in the cell cycle. Mol. Cell. Biol. 11, 4045–4052.
Bahler, J. and Nurse, P. (2001) Fission yeast Pom1p kinase activity is cell cycle regulated and essential for cellular symmetry during growth and division. EMBO J. 20, 1064–1073.
Souza, G. M., da Silva, A. M., and Kuspa, A. (1999) Starvation promotes Dictyostelium development by relieving PufA inhibition of PKA translation through the YakA kinase pathway. Development 126, 3263–3274.
Alvarez, M., Estivill, X., and de la Luna, S. (2003) DYRK1A accumulates in splicing speckles through a novel targeting signal and induces speckle disassembly. J. Cell Sci. 116, 3099–3107.
Hammerle, B., Carnicero, A., Elizalde, C., Ceron, J., Martinez, S., and Tejedor, F. J. (2003) Expression patterns and subcellular localization of the Down syndrome candidate protein MNB/DYRK1A suggest a role in late neuronal differentiation. Eur. J. Neurosci. 17, 2277–2286.
Marti, E., Altafaj, X., Dierssen, M., et al. (2003) Dyrk1A expression pattern supports specific roles of this kinase in the adult central nervous system. Brain Res. 964, 250–263.
Wegiel, J., Kuchna, I., Nowicki, K., et al. (2004) Cell type-and brain structure-specific patterns of distribution of minibrain kinase in human brain. Brain Res. 1010, 69–80.
Deng, X., Ewton, D. Z., Li, S. (2006) The kinase Mirk/Dyrk1B mediates cell survival in pancreatic ductal adenocarcinoma. Cancer Res. in press.
Mercer, S. E., Ewton, D. Z., Shah, S., Naqvi, A. and Friedman, E. (2006) Mirk/Dyrk 1B mediates cell wurvival in rabdomyosarcomas. Cancer Res., in press.
Miyata, Y. and Nishida, E. (1999) Distantly related cousins of MAP kinase: biochemical properties and possible physiological functions. Biochem. Biophys. Res. Commun. 266, 291–295.
Himpel, S., Panzer, P., Eirmbter, K., et al. (2001) Identification of the autophosphorylation sites and characterization of their effects in the protein kinase DYRK1A. Biochem. J. 359, 497–505.
Lochhead, P. A., Sibbet, G., Morrice, N., and Cleghon, V. (2005) Activation-loop autophosphorylation is mediated by a novel transitional intermediate form of DYRKs. Cell 121, 925–936.
Campbell, L. E. and Proud, C. G. (2002) Differing substrate specificities of members of the DYRK family of arginine-directed protein kinases. FEBS Lett 510, 31–36.
Himpel, S., Tegge, W., Frank, R., Leder, S., Joost, H. G., and Becker, W. (2000) Specificity determinants of substrate recognition by the protein kinase DYRK1A. J. Biol. Chem. 275, 2431–2438.
Deng, X., Mercer, S. E., Shah, S., Ewton, D. Z., and Friedman, E. (2004) The cyclin-dependent kinase inhibitor p27Kip1 is stabilized in G(0) by Mirk/Dyrk1B kinase. J. Biol. Chem. 279, 22,498–22,504.
Deng, X., Ewton, D. Z., Mercer, S. E., and Friedman, E. (2005) Mirk/Dyrk1B decreases the nuclear accumulation of class II histone deacetylases during skeletal muscle differentiation. J. Biol. Chem. 280, 4894–4905.
Lim, S., Jin, K., and Friedman, E. (2002) Mirk protein kinase is activated by MKK3 and functions as a transcriptional activator of HNF1alpha. J. Biol. Chem. 277, 25,040–25,046.
Zou, Y., Ewton, D. Z., Deng, X., Mercer, S. E., and Friedman, E. (2004) Mirk/Dyrk1B kinase destabilizes cyclin D1 by phosphorylation at threonine 288. J. Biol. Chem. 279, 27,790–27,798.
Skurat, A. V. and Dietrich, A. D. (2004) Phosphorylation of Ser640 in muscle glycogen synthase by DYRK family protein kinases. J. Biol. Chem. 279, 2490–2498.
Leder, S., Czajkowska, H., Maenz, B., et al. (2003) Alternative splicing variants of dual specificity tyrosine phosphorylated and regulated kinase 1B exhibit distinct patterns of expression and functional properties. Biochem. J. 372, 881–888.
Deng, X., Ewton, D., Pawlikowski, B., Maimone, M., and Friedman, E. (2003) Mirk/Dyrk1B is a rho-induced kinase active in skeletal muscle differentiation. J. Biol. Chem. 278, 41,347–41,354.
Rogers, S., Wells, R., Rechsteiner, M. (1986) Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis. Science 234, 364–368.
Rechsteiner, M. and Rogers, S. W. (1996) PEST sequences and regulation by proteolysis. Trends Biochem. Sci. 21, 267–271.
Lim, S., Zou, Y., and Friedman, E. (2002) The transcriptional activator Mirk/Dyrk1B is sequestered by p38alpha/beta MAP kinase. J. Biol. Chem. 277, 49,438–49,445.
Nadal-Ginard, B., Kajstura, J., Leri, A., and Anversa, P. (2003) Myocyte death, growth, and regeneration in cardiac hypertrophy and failure. Circ. Res. 92, 139–150.
Solloway, M. J. and Harvey, R. P. (2003) Molecular pathways in myocardial development: a stem cell perspective. Cardiovasc. Res. 58, 264–277.
Urbanek, K., Quaini, F., Tasca, G., et al. (2003) Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc. Natl. Acad. Sci. USA 100, 10,440–10,445.
Beltrami, A. P., Barlucchi, L., Torella, D., et al. (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114, 763–776.
Ewton, D. Z., Lee, K., Deng, X., Lim, S., and Friedman, E. (2003) Rapid turnover of cell-cycle regulators found in Mirk/Dyrk1B transfectants. Int. J. Cancer 103, 21–28.
Lu, J., McKinsey, T. A., Nicol, R. L., and Olson, E. N. (2000) Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases. Proc. Natl. Acad. Sci. USA 97, 4070–4075.
McKinsey, T. A., Zhang, C. L., and Olson, E. N. (2001) Control of muscle development by dueling HATs and HDACs. Curr. Opin. Genet. Dev. 11, 497–504.
Lu, J., McKinsey, T. A., Zhang, C. L., and Olson, E. N. (2000) Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases. Mol Cell 6, 233–244.
Asada, M., Yamada, T., Ichijo, H., et al. (1999) Apoptosis inhibitory activity of cytoplasmic p21(Cip1/WAF1) in monocytic differentiation. EMBO J. 18, 1223–1234.
Zhou, B., Liao, Y., Xia, W., Lee, M.-H., and Hung, M.-C. (2001) Cytoplasmic localization of p21cip1/waf1 by Aktinduced phosphorylation in HER-2/Neu-overexpressing cells. Nat. Cell Biol. 3, 245–252.
Xia, W., Chen, J. S., Zhou, X., et al. (2004) Phosphorylation/cytoplasmic localization of p21Cip1/WAF1 is associated with HER2/neu overexpression and provides a novel combination predictor for poor prognosis in breast cancer patients. Clin. Cancer Res. 10, 3815–3824.
Blagosklonny, M. V. (2002) Are p27 and p21 cytoplasmic oncoproteins? Cell Cycle 1, 391–393.
Wang J. and Walsh, K. (1996) Resistance to apoptosis conferred by Cdk inhibitors during myocyte differentiation. Science 273, 359–361.
Tanaka, H., Yamashita, T., Asada, M., Mizutani, S., Yoshikawa, H., and Tohyama, M. (2002) Cytoplasmic p21(Cip1/WAF1) regulates neurite remodeling by inhibiting Rho-kinase activity. J. Cell Biol. 158, 321–329.
Tanaka, H., Yamashita, T., Yachi, K., Fujiwara, T., Yoshikawa, H., and Tohyama, M. (2004) Cytoplasmic p21(Cip1/WAF1) enhances axonal regeneration and functional recovery after spinal cord injury in rats. Neuroscience 127, 155–164.
Merlino, G. and Helman, L. J. (1999) Rhabdomyosarcoma-working out the pathways. Oncogene. 18, 5340–5348.
Kumar, R. and Hung, M. C. (2005). Signaling intricacies take center stage in cancer cells. Cancer Res. 65, 2511–2515.
Vivanco, I. and Sawyers, C. L. (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489–501.
Eskinazi, R., Thony, B., Svoboda M., et al. (1999) Overexpression of pterin-4a-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 in human colon cancer. Am. J. Pathol. 155, 1105–1113.
Zou, Y., Lim, S., Lee, K., Deng, X., and Friedman, E. (2003) Mirk/Dyrk1B is an inhibitor of epithelial cell migration which negatively regulated by the Met-adaptor ran BPM. J. Biol. Chem. 278, 49,573–49,581.
Wang, D., Li, Z., Messing, E. M., and Wu, G. (2002) Activation of Ras/Erk pathway by a novel MET-interacting protein RanBPM. J. Biol. Chem. 277, 36,216–36,222.
Ferracini, R., Olivero, M., Di Renzo, M. F., et al. (1996) Retrogenic expression of the MET proto-oncogene correlates with the invasive phenotype of human rhabdomyosarcomas. Oncogene 12, 1697–1705.
Sharp, R., Recio, J. A., Jhappan, C., et al. (2002) Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis. Nat. Med. 8, 1276–1280.
Takayama, H., LaRochelle, W. J., Sharp, R., et al. (1997) Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. Proc. Natl. Acad. Sci. USA 94, 701–706.
Yaffe, M. B. (2002) How do 14-3-3 proteins work?—Gatekeeper phosphorylation and the molecular anvil hypothesis. FEBS Lett. 513, 53–57.
Kim, D., Won, J., Shin, D. W., et al. (2004) Regulation of Dyrk1A kinase activity by 14-3-3. Biochem. Biophys. Res. Commun. 323, 499–504.
Hawke, T. J., Meeson, A. P., Jiang, N., et al. (2003) p21 is essential for normal myogenic progenitor cell function in regenerating skeletal muscle. Am. J. Physiol. 285, C1019-C1027.
Sordella, R., Bell, D. W., Haber, D. A., and Settleman, J. (2004) Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305, 1163–1167.
Uzgare, A. R. and Isaacs, J. T. (2004) Enhanced redundancy in Akt and mitogen-activated protein kinaseinduced survival of malignant versus normal prostate epithelial cells. Cancer Res. 64, 6190–6199.
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Mercer, S.E., Friedman, E. Mirk/Dyrk 1B. Cell Biochem Biophys 45, 303–315 (2006). https://doi.org/10.1385/CBB:45:3:303
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DOI: https://doi.org/10.1385/CBB:45:3:303