NDR kinases regulate essential cell processes from yeast to humans

Nature Reviews Molecular Cell Biology - Tập 7 Số 4 - Trang 253-264 - 2006
Alexander Hergovich1, Mario Stegert, Debora Schmitz, Brian A. Hemmings
1Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland

Tóm tắt

Từ khóa


Tài liệu tham khảo

Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912?1934 (2002).

Colman-Lerner, A., Chin, T. E. & Brent, R. Yeast Cbk1 and Mob2 activate daughter-specific genetic programs to induce asymmetric cell fates. Cell 107, 739?750 (2001).

Du, L. L. & Novick, P. Pag1p, a novel protein associated with protein kinase Cbk1p, is required for cell morphogenesis and proliferation in Saccharomyces cerevisiae. Mol. Biol. Cell 13, 503?514 (2002).

Hou, M. C., Guertin, D. A. & McCollum, D. Initiation of cytokinesis is controlled through multiple modes of regulation of the Sid2p-Mob1p kinase complex. Mol. Cell Biol. 24, 3262?3276 (2004).

Hou, M. C., Salek, J. & McCollum, D. Mob1p interacts with the Sid2p kinase and is required for cytokinesis in fission yeast. Curr. Biol. 10, 619?622 (2000).

Hou, M. C., Wiley, D. J., Verde, F. & McCollum, D. Mob2p interacts with the protein kinase Orb6p to promote coordination of cell polarity with cell cycle progression. J. Cell Sci. 116, 125?135 (2003).

Komarnitsky, S. I. et al. DBF2 protein kinase binds to and acts through the cell cycle-regulated MOB1 protein. Mol. Cell Biol. 18, 2100?2107 (1998).

Mah, A. S., Jang, J. & Deshaies, R. J. Protein kinase Cdc15 activates the Dbf2?Mob1 kinase complex. Proc. Natl Acad. Sci. USA 98, 7325?7330 (2001). Established how Cdc15 regulates the Dbf2p?Mob1p complex at the molecular level, which substantiated previously published genetic data with solid biochemical evidence.

Stoepel, J., Ottey, M. A., Kurischko, C., Hieter, P. & Luca, F. C. The mitotic exit network Mob1p?Dbf2p kinase complex localizes to the nucleus and regulates passenger protein localization. Mol. Biol. Cell 16, 5465?5479 (2005).

Weiss, E. L. et al. The Saccharomyces cerevisiae Mob2p?Cbk1p kinase complex promotes polarized growth and acts with the mitotic exit network to facilitate daughter cell-specific localization of Ace2p transcription factor. J. Cell Biol. 158, 885?900 (2002).

Emoto, K. et al. Control of dendritic branching and tiling by the Tricornered-kinase/Furry signaling pathway in Drosophila sensory neurons. Cell 119, 245?256 (2004). This report, together with reference 12, shows that NDR kinases are essential for the control of dendritic tiling in invertebrates.

Gallegos, M. E. & Bargmann, C. I. Mechanosensory neurite termination and tiling depend on SAX-2 and the SAX-1 kinase. Neuron 44, 239?249 (2004).

Harvey, K. F., Pfleger, C. M. & Hariharan, I. K. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114, 457?467 (2003). This article, together with references 17,19?21, describes the discovery of the Hpo signalling network in D. melanogaster.

He, Y. et al. Drosophila Mob family proteins interact with the related Tricornered (Trc) and Warts (Wts) kinases. Mol. Biol. Cell 16, 4139?4152 (2005).

He, Y., Fang, X., Emoto, K., Jan, Y. N. & Adler, P. N. The tricornered Ser/Thr protein kinase is regulated by phosphorylation and interacts with furry during Drosophila wing hair development. Mol. Biol. Cell 16, 689?700 (2005).

Huang, J., Wu, S., Barrera, J., Matthews, K. & Pan, D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila homolog of YAP. Cell 122, 421?434 (2005). Shows that Yki is a downstream target of Hpo signalling in D. melanogaster , thereby linking Lats activity to transcriptional regulation.

Jia, J., Zhang, W., Wang, B., Trinko, R. & Jiang, J. The Drosophila Ste20 family kinase dMST functions as a tumor suppressor by restricting cell proliferation and promoting apoptosis. Genes Dev. 17, 2514?2519 (2003).

Lai, Z. C. et al. Control of cell proliferation and apoptosis by Mob as tumor suppressor, Mats. Cell 120, 675?685 (2005). Provides evidence that, in D. melanogaster , Lats is regulated by physically binding to dMob1/Mats.

Pantalacci, S., Tapon, N. & Leopold, P. The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nature Cell Biol. 5, 921?927 (2003).

Udan, R. S., Kango-Singh, M., Nolo, R., Tao, C. & Halder, G. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nature Cell Biol. 5, 914?920 (2003).

Wu, S., Huang, J., Dong, J. & Pan, D. Hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell 114, 445?456 (2003).

Bichsel, S. J., Tamaskovic, R., Stegert, M. R. & Hemmings, B. A. Mechanism of activation of NDR (nuclear Dbf2-related) protein kinase by the hMOB1 protein. J. Biol. Chem. 279, 35228?35235 (2004).

Chan, E. H. et al. The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene 24, 2076?2086 (2005).

Devroe, E., Erdjument-Bromage, H., Tempst, P. & Silver, P. A. Human Mob proteins regulate the NDR1 and NDR2 serine-threonine kinases. J. Biol. Chem. 279, 24444?24451 (2004).

Devroe, E., Silver, P. A. & Engelman, A. HIV-1 incorporates and proteolytically processes human NDR1 and NDR2 serine-threonine kinases. Virology 331, 181?189 (2005).

Hergovich, A., Bichsel, S. J. & Hemmings, B. A. Human NDR kinases are rapidly activated by MOB proteins through recruitment to the plasma membrane and phosphorylation. Mol. Cell Biol. 25, 8259?8272 (2005).

Millward, T. A., Heizmann, C. W., Schafer, B. W. & Hemmings, B. A. Calcium regulation of Ndr protein kinase mediated by S100 calcium-binding proteins. EMBO J. 17, 5913?5922 (1998).

Millward, T. A., Hess, D. & Hemmings, B. A. Ndr protein kinase is regulated by phosphorylation on two conserved sequence motifs. J. Biol. Chem. 274, 33847?33850 (1999).

Stegert, M. R., Hergovich, A., Tamaskovic, R., Bichsel, S. J. & Hemmings, B. A. Regulation of NDR protein kinase by hydrophobic motif phosphorylation mediated by the mammalian Ste20-like kinase MST3. Mol. Cell Biol. 25, 11019?11029 (2005). Shows that human NDR1/2 are specifically phosphorylated on the hydrophobic motif, and not the activation segment, by MST3 kinase.

Stegert, M. R., Tamaskovic, R., Bichsel, S. J., Hergovich, A. & Hemmings, B. A. Regulation of NDR2 protein kinase by multi-site phosphorylation and the S100B calcium-binding protein. J. Biol. Chem. 279, 23806?23812 (2004).

Tamaskovic, R., Bichsel, S. J., Rogniaux, H., Stegert, M. R. & Hemmings, B. A. Mechanism of Ca2+-mediated regulation of NDR protein kinase through autophosphorylation and phosphorylation by an upstream kinase. J. Biol. Chem. 278, 6710?6718 (2003).

Bidlingmaier, S., Weiss, E. L., Seidel, C., Drubin, D. G. & Snyder, M. The Cbk1p pathway is important for polarized cell growth and cell separation in Saccharomyces cerevisiae. Mol. Cell Biol. 21, 2449?2462 (2001).

Geyer, C. R., Colman-Lerner, A. & Brent, R. ?Mutagenesis? by peptide aptamers identifies genetic network members and pathway connections. Proc. Natl Acad. Sci. USA 96, 8567?8572 (1999).

Johnston, L. H., Eberly, S. L., Chapman, J. W., Araki, H. & Sugino, A. The product of the Saccharomyces cerevisiae cell cycle gene DBF2 has homology with protein kinases and is periodically expressed in the cell cycle. Mol. Cell Biol. 10, 1358?1366 (1990).

Racki, W. J., Becam, A. M., Nasr, F. & Herbert, C. J. Cbk1p, a protein similar to the human myotonic dystrophy kinase, is essential for normal morphogenesis in Saccharomyces cerevisiae. EMBO J. 19, 4524?4532 (2000).

Sparks, C. A., Morphew, M. & McCollum, D. Sid2p, a spindle pole body kinase that regulates the onset of cytokinesis. J. Cell Biol. 146, 777?790 (1999).

Toyn, J. H. & Johnston, L. H. The Dbf2 and Dbf20 protein kinases of budding yeast are activated after the metaphase to anaphase cell cycle transition. EMBO J. 13, 1103?1113 (1994).

Verde, F., Wiley, D. J. & Nurse, P. Fission yeast orb6, a ser/thr protein kinase related to mammalian rho kinase and myotonic dystrophy kinase, is required for maintenance of cell polarity and coordinates cell morphogenesis with the cell cycle. Proc. Natl Acad. Sci. USA 95, 7526?7531 (1998).

Geng, W., He, B., Wang, M. & Adler, P. N. The tricornered gene, which is required for the integrity of epidermal cell extensions, encodes the Drosophila nuclear DBF2-related kinase. Genetics 156, 1817?1828 (2000).

Justice, R. W., Zilian, O., Woods, D. F., Noll, M. & Bryant, P. J. The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev. 9, 534?546 (1995).

McPherson, J. P. et al. Lats2/Kpm is required for embryonic development, proliferation control and genomic integrity. EMBO J. 23, 3677?3688 (2004).

St John, M. A. et al. Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nature Genet. 21, 182?186 (1999). Shows that Lats1 null mice spontaneously develop tumours and are hypersensitive to carcinogenic treatments.

Xu, T., Wang, W., Zhang, S., Stewart, R. A. & Yu, W. Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121, 1053?1063 (1995).

Zallen, J. A., Peckol, E. L., Tobin, D. M. & Bargmann, C. I. Neuronal cell shape and neurite initiation are regulated by the Ndr kinase SAX-1, a member of the Orb6/COT-1/warts serine/threonine kinase family. Mol. Biol. Cell 11, 3177?3190 (2000).

Hisaoka, M., Tanaka, A. & Hashimoto, H. Molecular alterations of h-warts/LATS1 tumor suppressor in human soft tissue sarcoma. Lab Invest. 82, 1427?1435 (2002).

Takahashi, Y. et al. Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. Clin. Cancer Res. 11, 1380?1385 (2005).

Adeyinka, A. et al. Analysis of gene expression in ductal carcinoma in situ of the breast. Clin. Cancer Res. 8, 3788?3795 (2002).

Ross, D. T. et al. Systematic variation in gene expression patterns in human cancer cell lines. Nature Genet. 24, 227?235 (2000).

Hanks, S. K. & Hunter, T. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 9, 576?596 (1995). Concisely defines and illustrates the structure of the catalytic domain of protein kinases.

Millward, T., Cron, P. & Hemmings, B. A. Molecular cloning and characterization of a conserved nuclear serine(threonine) protein kinase. Proc. Natl Acad. Sci. USA 92, 5022?5026 (1995). The first molecular description of an NDR kinase.

Bothos, J., Tuttle, R. L., Ottey, M., Luca, F. C. & Halazonetis, T. D. Human LATS1 is a mitotic exit network kinase. Cancer Res. 65, 6568?6575 (2005).

Frenz, L. M., Lee, S. E., Fesquet, D. & Johnston, L. H. The budding yeast Dbf2 protein kinase localises to the centrosome and moves to the bud neck in late mitosis. J. Cell Sci. 113, 3399?3408 (2000).

Visintin, R. & Amon, A. Regulation of the mitotic exit protein kinases Cdc15 and Dbf2. Mol. Biol. Cell 12, 2961?2974 (2001).

Nelson, B. et al. RAM: a conserved signaling network that regulates Ace2p transcriptional activity and polarized morphogenesis. Mol. Biol. Cell 14, 3782?3803 (2003). This article, together with reference 79, provides evidence for the existence of a morphogenesis?RAM network in yeast.

Salimova, E., Sohrmann, M., Fournier, N. & Simanis, V. The S. pombe orthologue of the S. cerevisiae mob1 gene is essential and functions in signalling the onset of septum formation. J. Cell Sci. 113, 1695?1704 (2000).

Hirata, D. et al. Fission yeast Mor2/Cps12, a protein similar to Drosophila Furry, is essential for cell morphogenesis and its mutation induces Wee1-dependent G(2) delay. EMBO J. 21, 4863?4874 (2002).

Wiley, D. J., Marcus, S., D'Urso, G. & Verde, F. Control of cell polarity in fission yeast by association of Orb6p kinase with the highly conserved protein methyltransferase Skb1p. J. Biol. Chem. 278, 25256?25263 (2003).

Mikeladze-Dvali, T. et al. The growth regulators warts/lats and melted interact in a bistable loop to specify opposite fates in Drosophila R8 photoreceptors. Cell 122, 775?787 (2005).

Stork, O. et al. Neuronal functions of the novel serine/threonine kinase Ndr2. J. Biol. Chem. 279, 45773?45781 (2004).

Toji, S. et al. The centrosomal protein Lats2 is a phosphorylation target of Aurora-A-kinase. Genes Cells 9, 383?397 (2004).

Hirota, T. et al. Zyxin, a regulator of actin filament assembly, targets the mitotic apparatus by interacting with h-warts/LATS1 tumor suppressor. J. Cell Biol. 149, 1073?1086 (2000).

Yang, J. et al. Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation. Mol. Cell 9, 1227?1240 (2002).

Bhattacharya, S., Large, E., Heizmann, C. W., Hemmings, B. & Chazin, W. J. Structure of the Ca2+/S100B/NDR kinase peptide complex: insights into S100 target specificity and activation of the kinase. Biochemistry 42, 14416?14426 (2003).

Luca, F. C. & Winey, M. MOB1, an essential yeast gene required for completion of mitosis and maintenance of ploidy. Mol. Biol. Cell 9, 29?46 (1998). Describes the identification of Mob1p, the founding member of the Mob family.

Lee, S. E., Frenz, L. M., Wells, N. J., Johnson, A. L. & Johnston, L. H. Order of function of the budding-yeast mitotic exit-network proteins Tem1, Cdc15, Mob1, Dbf2, and Cdc5. Curr. Biol. 11, 784?788 (2001).

Ponchon, L., Dumas, C., Kajava, A. V., Fesquet, D. & Padilla, A. NMR solution structure of Mob1, a mitotic exit network protein and its interaction with an NDR kinase peptide. J. Mol. Biol. 337, 167?182 (2004).

Stavridi, E. S. et al. Crystal structure of a human Mob1 protein: toward understanding Mob-regulated cell cycle pathways. Structure (Camb) 11, 1163?1170 (2003).

Tapon, N. et al. Salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110, 467?478 (2002).

Hayette, S. et al. AF4p12, a human homologue to the furry gene of Drosophila, as a novel MLL fusion partner. Cancer Res. 65, 6521?6525 (2005).

Bardin, A. J. & Amon, A. Men and sin: what's the difference? Nature Rev. Mol. Cell Biol. 2, 815?826 (2001). Summarises the MEN/SIN pathways in budding and fission yeast.

Bosl, W. J. & Li, R. Mitotic-exit control as an evolved complex system. Cell 121, 325?333 (2005).

McCollum, D. & Gould, K. L. Timing is everything: regulation of mitotic exit and cytokinesis by the MEN and SIN. Trends Cell Biol. 11, 89?95 (2001).

Wang, Y. & Ng, T. Y. Phosphatase 2A negatively regulates mitotic exit in Saccharomyces cerevisiae. Mol. Biol. Cell 17, 80?89 (2005).

Daga, R. R., Lahoz, A., Munoz, M. J., Moreno, S. & Jimenez, J. Etd1p is a novel protein that links the SIN cascade with cytokinesis. EMBO J. 24, 2436?2446 (2005).

Mailand, N. et al. Deregulated human Cdc14A phosphatase disrupts centrosome separation and chromosome segregation. Nature Cell Biol. 4, 317?322 (2002).

Tao, W. et al. Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. Nature Genet. 21, 177?181 (1999).

Yang, X. et al. LATS1 tumour suppressor affects cytokinesis by inhibiting LIMK1. Nature Cell Biol. 6, 609?617 (2004).

Vazquez-Novelle, M. D., Esteban, V., Bueno, A. & Sacristan, M. P. Functional homology among human and fission yeast Cdc14 phosphatases. J. Biol. Chem. 280, 29144?29150 (2005).

Kanai, M. et al. Fission yeast MO25 protein is localized at SPB and septum and is essential for cell morphogenesis. EMBO J. 24, 3012?3025 (2005).

Green, D. R. & Evan, G. I. A matter of life and death. Cancer Cell 1, 19?30 (2002).

Kango-Singh, M. et al. Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. Development 129, 5719?5730 (2002).

Jimenez-Velasco, A. et al. Downregulation of the large tumor suppressor 2 (LATS2/KPM) gene is associated with poor prognosis in acute lymphoblastic leukemia. Leukemia 19, 2347?2350 (2005).

Cheung, W. L. et al. Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase. Cell 113, 507?517 (2003). This communication, together with references 86 and 89, establishes how MST1 kinase triggers pro-apoptotic events.

Deng, Y., Pang, A. & Wang, J. H. Regulation of mammalian STE20-like kinase 2 (MST2) by protein phosphorylation/dephosphorylation and proteolysis. J. Biol. Chem. 278, 11760?11767 (2003).

Graves, J. D., Draves, K. E., Gotoh, Y., Krebs, E. G. & Clark, E. A. Both phosphorylation and caspase-mediated cleavage contribute to regulation of the Ste20-like protein kinase Mst1 during CD95/Fas-induced apoptosis. J. Biol. Chem. 276, 14909?14915 (2001).

Graves, J. D. et al. Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. EMBO J. 17, 2224?2234 (1998).

Lee, K. K., Ohyama, T., Yajima, N., Tsubuki, S. & Yonehara, S. MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation. J. Biol. Chem. 276, 19276?19285 (2001).

Lin, Y., Khokhlatchev, A., Figeys, D. & Avruch, J. Death-associated protein 4 binds MST1 and augments MST1-induced apoptosis. J. Biol. Chem. 277, 47991?48001 (2002).

Ura, S., Masuyama, N., Graves, J. D. & Gotoh, Y. Caspase cleavage of MST1 promotes nuclear translocation and chromatin condensation. Proc. Natl Acad. Sci. USA 98, 10148?10153 (2001).

Khokhlatchev, A. et al. Identification of a novel Ras-regulated proapoptotic pathway. Curr. Biol. 12, 253?265 (2002).

O'Neill, E., Rushworth, L., Baccarini, M. & Kolch, W. Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science 306, 2267?2270 (2004).

Praskova, M., Khoklatchev, A., Ortiz-Vega, S. & Avruch, J. Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras. Biochem. J. 381, 453?462 (2004).

Kamikubo, Y., Takaori-Kondo, A., Uchiyama, T. & Hori, T. Inhibition of cell growth by conditional expression of kpm, a human homologue of Drosophila warts/lats tumor suppressor. J. Biol. Chem. 278, 17609?17614 (2003).

Li, Y. et al. Lats2, a putative tumor suppressor, inhibits G1/S transition. Oncogene 22, 4398?4405 (2003).

Yang, X., Li, D. M., Chen, W. & Xu, T. Human homologue of Drosophila lats, LATS1, negatively regulate growth by inducing G(2)/M arrest or apoptosis. Oncogene 20, 6516?6523 (2001).

Sudol, M. Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product. Oncogene 9, 2145?2152 (1994).

Strano, S. et al. The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage. Mol. Cell 18, 447?459 (2005).

Cong, J. et al. The furry gene of Drosophila is important for maintaining the integrity of cellular extensions during morphogenesis. Development 128, 2793?2802 (2001).

Devries, S. H. & Baylor, D. A. Mosaic arrangement of ganglion cell receptive fields in rabbit retina. J. Neurophysiol. 78, 2048?2060 (1997).

Dan, I., Watanabe, N. M. & Kusumi, A. The Ste20 group kinases as regulators of MAP kinase cascades. Trends Cell Biol. 11, 220?230 (2001).

Glantschnig, H., Rodan, G. A. & Reszka, A. A. Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylation. J. Biol. Chem. 277, 42987?42996 (2002).

Lee, K. K. & Yonehara, S. Phosphorylation and dimerization regulate nucleocytoplasmic shuttling of mammalian STE20-like kinase (MST). J. Biol. Chem. 277, 12351?12358 (2002).

Dan, I. et al. Cloning of MASK, a novel member of the mammalian germinal center kinase III subfamily, with apoptosis-inducing properties. J. Biol. Chem. 277, 5929?5939 (2002).

Huang, C. Y. et al. Caspase activation of mammalian sterile 20-like kinase 3 (Mst3). Nuclear translocation and induction of apoptosis. J. Biol. Chem. 277, 34367?34374 (2002).

Preisinger, C. et al. YSK1 is activated by the Golgi matrix protein GM130 and plays a role in cell migration through its substrate 14-3-3ζ. J. Cell Biol. 164, 1009?1020 (2004).

Rabizadeh, S. et al. The scaffold protein CNK1 interacts with the tumor suppressor RASSF1A and augments RASSF1A-induced cell death. J. Biol. Chem. 279, 29247?29254 (2004).

Bardin, A. J., Boselli, M. G. & Amon, A. Mitotic exit regulation through distinct domains within the protein kinase Cdc15. Mol. Cell Biol. 23, 5018?5030 (2003).

Gruneberg, U., Campbell, K., Simpson, C., Grindlay, J. & Schiebel, E. Nud1p links astral microtubule organization and the control of exit from mitosis. EMBO J. 19, 6475?6488 (2000).

Jaspersen, S. L., Charles, J. F., Tinker-Kulberg, R. L. & Morgan, D. O. A late mitotic regulatory network controlling cyclin destruction in Saccharomyces cerevisiae. Mol. Biol. Cell 9, 2803?2817 (1998).

Xu, S., Huang, H. K., Kaiser, P., Latterich, M. & Hunter, T. Phosphorylation and spindle pole body localization of the Cdc15p mitotic regulatory protein kinase in budding yeast. Curr. Biol. 10, 329?332 (2000).

Hauschild, A. et al. S100B protein detection in serum is a significant prognostic factor in metastatic melanoma. Oncology 56, 338?344 (1999).

Suzuki, T. et al. New genes involved in cancer identified by retroviral tagging. Nature Genet. 32, 166?174 (2002).

Wang, D., Harper, J. F. & Gribskov, M. Systematic trans-genomic comparison of protein kinases between Arabidopsis and Saccharomyces cerevisiae. Plant Physiol. 132, 2152?2165 (2003).

Verde, F., Mata, J. & Nurse, P. Fission yeast cell morphogenesis: identification of new genes and analysis of their role during the cell cycle. J. Cell Biol. 131, 1529?1538 (1995).

Gorovits, R., Propheta, O., Kolot, M., Dombradi, V. & Yarden, O. A mutation within the catalytic domain of COT1 kinase confers changes in the presence of two COT1 isoforms and in Ser/Thr protein kinase and phosphatase activities in Neurospora crassa. Fungal Genet. Biol. 27, 264?274 (1999).

Yarden, O., Plamann, M., Ebbole, D. J. & Yanofsky, C. cot-1, a gene required for hyphal elongation in Neurospora crassa, encodes a protein kinase. EMBO J. 11, 2159?2166 (1992).

Scheffer, J., Ziv, C., Yarden, O. & Tudzynski, P. The COT1 homologue CPCOT1 regulates polar growth and branching and is essential for pathogenicity in Claviceps purpurea. Fungal Genet. Biol. 42, 107?118 (2005).

Buhr, T. L. et al. A kinase-encoding gene from Colletotrichum trifolii complements a colonial growth mutant of Neurospora crassa. Mol. Gen. Genet. 251, 565?572 (1996).

Durrenberger, F. & Kronstad, J. The ukc1 gene encodes a protein kinase involved in morphogenesis, pathogenicity and pigment formation in Ustilago maydis. Mol. Gen. Genet. 261, 281?289 (1999).

McNemar, M. D. & Fonzi, W. A. Conserved serine/threonine kinase encoded by CBK1 regulates expression of several hypha-associated transcripts and genes encoding cell wall proteins in Candida albicans. J. Bacteriol. 184, 2058?2061 (2002).

Kottom, T. J. & Limper, A. H. Pneumocystis carinii cell wall biosynthesis kinase gene CBK1 is an environmentally responsive gene that complements cell wall defects of cbk-deficient yeast. Infect. Immun. 72, 4628?4636 (2004).

Garcia-Salcedo, J. A., Nolan, D. P., Gijon, P., Gomez-Rodriguez, J. & Pays, E. A protein kinase specifically associated with proliferative forms of Trypanosoma brucei is functionally related to a yeast kinase involved in the co-ordination of cell shape and division. Mol. Microbiol. 45, 307?319 (2002).

Hammarton, T. C., Lillico, S. G., Welburn, S. C. & Mottram, J. C. Trypanosoma brucei MOB1 is required for accurate and efficient cytokinesis but not for exit from mitosis. Mol. Microbiol. 56, 104?116 (2005).

Imai, T., Shimamura, S., Kurosaka, A., Yamagishi, H. & Terachi, T. Cloning and characterization of a novel radish protein kinase which is homologous to fungal cot-I-like and animal Ndr protein kinases. Genes Genet. Syst. 79, 283?291 (2004).

Lee, J. H., Van Montagu, M. & Verbruggen, N. A highly conserved kinase is an essential component for stress tolerance in yeast and plant cells. Proc. Natl Acad. Sci. USA 96, 5873?5877 (1999).

Kameshita, I. et al. Expression cloning of a variety of novel protein kinases in Lotus japonicus. J. Biochem. 137, 33?39 (2005).

Iida, S. et al. Tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G1 tetraploidy checkpoint function. Oncogene 23, 5266?5274 (2004).

Kuninaka, S. et al. The tumor suppressor WARTS activates the Omi/HtrA2-dependent pathway of cell death. Oncogene 24, 5287?5298 (2005).

Amente, S. et al. Identification of proteins interacting with the RNAPII FCP1 phosphatase: FCP1 forms a complex with arginine methyltransferase PRMT5 and it is a substrate for PRMT5-mediated methylation. FEBS Lett. 579, 683?689 (2005).

Luca, F. C. et al. Saccharomyces cerevisiae Mob1p is required for cytokinesis and mitotic exit. Mol. Cell Biol. 21, 6972?6983 (2001).

Yoshida, S., Asakawa, K. & Toh-e, A. Mitotic exit network controls the localization of Cdc14 to the spindle pole body in Saccharomyces cerevisiae. Curr. Biol. 12, 944?950 (2002).

Guertin, D. A., Chang, L., Irshad, F., Gould, K. L. & McCollum, D. The role of the sid1p kinase and cdc14p in regulating the onset of cytokinesis in fission yeast. EMBO J. 19, 1803?1815 (2000).

Morrell, J. L. et al. Sid4p-Cdc11p assembles the septation initiation network and its regulators at the S. pombe SPB. Curr. Biol. 14, 579?584 (2004).