Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

NDR kinases regulate essential cell processes from yeast to humans

Nature Reviews Molecular Cell Biology volume 7, pages 253–264 (2006)Cite this article

Key Points

  • The NDR (nuclear Dbf2-related) kinase family is conserved from yeast to humans, and is a subgroup of the serine/threonine AGC kinases. NDR kinases have important roles during mitotic progression, cytokinesis, morphological changes, cell proliferation and apoptosis.

  • The yeast NDR kinases, Dbf2p, Cbk1p, Sid2p and Orb6p, are functionally the best characterized members. They are essential components of signalling networks that control either morphological changes or mitotic exit.

  • In flies, large tumour suppressor (Lats; one out of the two Drosophila melanogaster NDR relatives) is a central component of the Hippo pathway, and regulates tissue growth. A similar pathway that controls cell proliferation and death might also exist in humans, but still needs to be verified experimentally.

  • NDR kinases are also important for dendritic/neurite outgrowth. Trc (tricornered) and SAX-1 (sensory axon guidance-1) (NDR kinases in D. melanogaster and Caenorhabditis elegans, respectively) are required for correct dendritic tiling.

  • The regulation of NDR kinases at the molecular level is best understood for the mammalian kinases NDR1 and NDR2. Autophosphorylation on Ser281 (activation segment) and phosphorylation on Thr444 (hydrophobic motif) of NDR1 by MST3 (a STE20-like kinase) is essential for kinase activation.

  • Interaction with its co-activator MOB (Msp1-one binder) through a conserved N-terminal domain is also an important step in the activation process of NDR kinases.

  • Members of the NDR protein-kinase family consist of an N-terminal domain (NTR, N-terminal regulatory domain), and have an insertion in their kinase domain between subdomains VII and VIII, therefore preceding the activation segment.

  • Two out of four mammalian NDR kinases, LATS1 and LATS2, function as tumour suppressors, whereas the other two members, NDR1 and NDR2, are probably proto-oncogenes.

  • Unravelling how LATS1/2 and NDR1/2 contribute to cellular transformation and consequently, the development of cancer, is an important challenge for the future.

Abstract

Members of the NDR (nuclear Dbf2-related) protein-kinase family are essential components of pathways that control important cellular processes, such as morphological changes, mitotic exit, cytokinesis, cell proliferation and apoptosis. Recent progress has shed light on the mechanisms that underlie the regulation and function of the NDR family members. Combined data from yeast, worms, flies, mice and human cells now highlight the conserved and important roles of the different NDR kinases in distinct cellular processes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Common characteristics of NDR kinases.
Figure 2: Regulation of NDR kinases at the molecular level in yeast and humans.
Figure 3: Control of cell death and proliferation by the Hpo?Lats pathway.

Similar content being viewed by others

References

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

    CAS  PubMed  Google Scholar 

  2. 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).

    Article  CAS  PubMed  Google Scholar 

  3. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

  6. 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).

    Article  CAS  PubMed  Google Scholar 

  7. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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.

    Article  CAS  PubMed  Google Scholar 

  12. 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).

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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.

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    Article  CAS  PubMed  Google Scholar 

  21. 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).

    Article  CAS  PubMed  Google Scholar 

  22. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. 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).

    Article  CAS  PubMed  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. 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).

    Article  CAS  PubMed  Google Scholar 

  32. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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.

    Article  CAS  PubMed  Google Scholar 

  43. 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).

    Article  CAS  PubMed  Google Scholar 

  44. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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).

    Article  CAS  PubMed  Google Scholar 

  46. 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).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  49. 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.

    Article  CAS  PubMed  Google Scholar 

  50. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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).

    Article  CAS  PubMed  Google Scholar 

  52. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 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).

    Article  CAS  PubMed  Google Scholar 

  56. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 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).

    Article  CAS  PubMed  Google Scholar 

  58. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  61. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  63. 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).

    Article  CAS  PubMed  Google Scholar 

  64. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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).

    Article  CAS  PubMed  Google Scholar 

  66. 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).

    Article  CAS  PubMed  Google Scholar 

  67. 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).

    Article  CAS  Google Scholar 

  68. 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).

    Article  CAS  PubMed  Google Scholar 

  69. 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).

    Article  CAS  PubMed  Google Scholar 

  70. 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.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  72. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  74. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  78. 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).

    Article  CAS  PubMed  Google Scholar 

  79. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  82. 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).

    Article  CAS  PubMed  Google Scholar 

  83. 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.

    Article  CAS  PubMed  Google Scholar 

  84. 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).

    Article  CAS  PubMed  Google Scholar 

  85. 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).

    Article  CAS  PubMed  Google Scholar 

  86. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 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).

    Article  CAS  PubMed  Google Scholar 

  88. 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).

    Article  CAS  PubMed  Google Scholar 

  89. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  91. 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).

    Article  CAS  PubMed  Google Scholar 

  92. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  95. 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).

    Article  CAS  PubMed  Google Scholar 

  96. 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).

    CAS  PubMed  Google Scholar 

  97. 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).

    Article  CAS  PubMed  Google Scholar 

  98. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  101. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  103. 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).

    Article  CAS  PubMed  Google Scholar 

  104. 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).

    Article  CAS  PubMed  Google Scholar 

  105. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 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).

    Article  CAS  PubMed  Google Scholar 

  107. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  113. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 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).

    Article  CAS  PubMed  Google Scholar 

  115. 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).

    Article  CAS  PubMed  Google Scholar 

  116. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 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).

    Article  CAS  PubMed  Google Scholar 

  118. 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).

    CAS  PubMed  Google Scholar 

  119. 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).

    Article  CAS  PubMed  Google Scholar 

  120. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 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).

    Article  CAS  PubMed  Google Scholar 

  123. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 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).

    Article  CAS  PubMed  Google Scholar 

  125. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  127. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  129. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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).

    Article  CAS  PubMed  Google Scholar 

  132. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 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).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We apologise to our colleagues whose work could not be included due to space limitations. We also thank P. King, J. Lisztwan and L. Tintignac for critical comments on the manuscript. The Hemmings laboratory is supported by the Swiss Cancer League. D. Schmitz is supported by the Boehringer Ingelheim Fonds. The Friedrich Miescher Institute is part of the Novartis Research Foundation.

Author information

Authors and Affiliations

  1. Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel, CH-4058, Switzerland

    Alexander Hergovich, Mario R. Stegert, Debora Schmitz & Brian A. Hemmings

Authors
  1. Alexander Hergovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mario R. Stegert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Debora Schmitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brian A. Hemmings
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brian A. Hemmings.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Related links

Related links

FURTHER INFORMATION

Brian Hemmings' homepage

Glossary

AGC kinases

A group of serine/threonine protein kinases, including AKT/protein kinase B, ribosomal S6 kinase and protein kinase C. Most AGC kinases must be phosphorylated on the activation segment and hydrophobic motif to render them fully active.

Activation segment

A segment near the entrance to the active site of both serine/threonine and tyrosine kinases. For many kinases, the activation segment must be phosphorylated on either a serine or threonine residue to achieve catalytic competence.

Cell growth

This term is usually used to describe an increase in the size of a population of cells. However, it should be strictly reserved for an increase in cytoplasmic/total volume of an individual cell.

Tumour-suppressor gene

A protective gene that normally limits the growth of tumours. When a tumour supressor is mutated, it may fail to keep a cancer from growing.

Oncogene

Mutated and/or overexpressed version of a normal gene of animal cells (the proto-oncogene) that in a dominant fashion can release the cell from normal restraints on growth, and therefore, alone or in concert with other changes, converts a cell into a tumour cell (cellular transformation).

Hydrophobic motif

Most AGC kinases contain a serine or threonine residue that is flanked by hydrophobic residues ? a typical FXXF motif is buried in a hydrophobic pocket. In most kinases, the hydrophobic motif locates C-terminal to the kinase's catalytic domain. Phosphorylation of the hydrophobic site is not only required for kinase activity, but also for kinase stabilization.

Spindle-pole body

The equivalent of centrosomes in lower eukaryotes. It is a plaque-shaped structure that is embedded in the nuclear membrane.

Centrosome

The centrosome is composed of two barrel-shaped structures, known as centrioles, that are surrounded by a pericentrosomal matrix. This is the main centre of microtubule nucleation.

Protein phosphatase type 2A

(PP2A). An essential serine/threonine phosphatase that is conserved in all eukaryotes. The core enzyme consists of a catalytic C and a regulatory A or B subunit. The diversity of the regulatory subunits allows PP2A to carry out various functions.

Hippo pathway

(Hpo pathway). A signalling cascade that consists of Sav, Hpo, Lats and dMob1 proteins and is essential for the control of tissue growth in D. melanogaster. Inactivating mutations in any cascade component result in tissue overgrowth.

Apoptosis

Also termed programmed cell death. In normally functioning cells, apoptosis is induced when dictated by age or state of cell health. This active process is often characterised by DNA fragmentation.

Scaffolding proteins

Anchoring proteins within close proximity of one another, which are thought to facilitate and to provide higher specificity for signal transmission (that is, tight regulation of phosphorylation and specific targeting of a site on the substrate because of the restricted orientation of the active site of the kinase and the substrates due to their binding to the scaffolding protein).

HEAT/Armadillo repeats

They are named after the following four molecules: huntingtin, elongation factor-3, PR65/A subunit of PP2A, and TOR (target of rapamycin) and are internal repetitions within proteins. HEAT/Armadillo repeats consist of α-helices, and include a series of conserved residues that form the repeats' hydrophobic cores.

Cytokinesis

The process of cytoplasmic cell division.

Dendritic tiling

Dendrites of a group of neurons innervate a tissue in a non-redundant manner, aiming to achieve maximal coverage of a sensory field with minimal overlaps.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hergovich, A., Stegert, M., Schmitz, D. et al. NDR kinases regulate essential cell processes from yeast to humans. Nat Rev Mol Cell Biol 7, 253–264 (2006). https://doi.org/10.1038/nrm1891

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1891

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing