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.

Inhibiting transient protein–protein interactions: lessons from the Cdc25 protein tyrosine phosphatases

Key Points

  • The eukaryotic cell cycle is controlled by the activity of many protein kinases and phosphatases. For example, the cell division cycle 25 (Cdc25) phosphatases dephosphorylate and thereby activate the cyclin-dependent kinase (CDK)–cyclin complexes.

  • Cdc25 phosphatases serve as potential targets for anticancer development because of their role in promoting cell-cycle progression and their frequent overexpression in various cancers.

  • The interactions of protein kinases and protein phosphatases with their protein substrates are transient, and are therefore poorly characterized and problematic for drug discovery.

  • A docking site remote from the active site in Cdc25 mediates efficient recognition of phosphorylated CDK–cyclins.

  • In a computationally derived and experimentally validated model of the docking orientation of CDC25B with its CDK–cyclin substrate, the interfacial contacts in the remote docking site are primarily ionic.

  • The remote docking site is as important to the in vivo function of CDC25B as the catalytic residues in the active site.

  • A pocket exists adjacent to the docking site on CDC25B to which potential inhibitors of this transient protein–protein interaction should be targeted.

  • Although deciphering the details of transient protein–protein interactions involved in cell-cycle control is difficult, a systematic and thorough approach can set the framework for the discovery and development of inhibitors that can serve as cancer therapeutics.

Abstract

Transient protein–protein interactions have key regulatory functions in many of the cellular processes that are implicated in cancerous growth, particularly the cell cycle. Targeting these transient interactions as therapeutic targets for anticancer drug development seems like a good idea, but it is not a trivial task. This Review discusses the issues and difficulties that are encountered when considering these transient interactions as drug targets, using the example of the cell division cycle 25 (Cdc25) phosphatases and their cyclin-dependent kinase (CDK)–cyclin protein substrates.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: The eukaryotic cell cycle.
Figure 2: Interfacial contacts of CDC25B.
Figure 3: CDC25B and the phospho-CDK2–cyclin A complex.

Similar content being viewed by others

References

  1. Carnero, A. Targeting the cell cycle for cancer therapy. Brit. J. Cancer 87, 129–133 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Aaronson, S. A. Growth factors and cancer. Science 254, 1146–1153 (1991).

    Article  CAS  PubMed  Google Scholar 

  3. Weinberg, R. A. Tumor suppressor genes. Science 254, 1138–1146 (1991).

    Article  CAS  PubMed  Google Scholar 

  4. Malumbres, M. & Barbacid, M. Mammalian cyclin-dependent kinases. Trends Biochem. Sci. 30, 630–641 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Morgan, D. O. Principles of CDK regulation. Nature 374, 131–134 (1995). An important review that summarizes the control of CDK activity by phosphorylation, the binding of cyclins and the binding of protein inhibitors.

    Article  CAS  PubMed  Google Scholar 

  6. Hoffmann, I., Draetta, G. & Karsenti, E. Activation of the phosphatase activity of human cdc25a by a cdk2-cyclin E dependent phosphorylation at the G1/S transition. EMBO J. 13, 4302–4310 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jinno, S. et al. Cdc25a is a novel phosphatase functioning early in the cell cycle. EMBO J. 13, 1549–1556 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Millar, J. B. A. et al. p55cdc25 is a nuclear protein required for the initiation of mitosis in human cells. Proc. Natl Acad. Sci. USA 88, 10500–10504 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hoffmann, I., Clarke, P. R., Marcote, M. J., Karsenti, E. & Draetta, G. Phosphorylation and activation of human cdc25c by cdc2-cyclin B and its involvement in the self-amplification of MPF at mitosis. EMBO J. 12, 53–63 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lammer, C. et al. The cdc25B phosphatase is essential for the G2/M phase transition in human cells. J. Cell Science 111, 2445–2453 (1998).

    CAS  PubMed  Google Scholar 

  11. Molinari, M., Mercurio, C., Dominguez, J., Goubin, F. & Draetta, G. F. Human Cdc25 A inactivation in response to S phase inhibition and its role in preventing premature mitosis. EMBO Rep. 1, 71–79 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mailand, N. et al. Regulation of G2/M events by Cdc25A through phosphorylation-dependent modulation of its stability. EMBO J. 21, 5911–5920 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chow, J. P. H. et al. Differential contribution of inhibitory phosphorylation of CDC2 and CDK2 for unperturbed cell cycle control and DNA integrity checkpoints. J. Biol. Chem. 278, 40815–40828 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Lindqvist, A., Kallstrom, H., Lundgren, A., Barsoum, E. & Rosenthal, C. K. Cdc25B cooperates with Cdc25A to induce mitosis but has a unique role in activating cyclin B1-Cdk2 at the centrosome. J. Cell Biol. 171, 35–45 (2005). Using siRNA the authors tease apart the relative contributions of CDC25A and CDC25B in triggering the G2–M transition.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ferguson, A. M., White, L. S., Donovan, P. J. & Piwnica-Worms, H. Normal cell cycle and checkpoint responses in mice and cells lacking Cdc25B and Cdc25C protein phosphatases. Mol. Cell Biol. 25, 2853–2860 (2005). Reports on the surprizing finding that CDC25A alone is capable of sustaining normal cell-cycle progression and mediating a normal response to DNA damage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Iliakis, G., Wang, Y., Guan, J. & Wang, H. DNA damage checkpoint control in cells exposed to ionizing radiation. Oncogene 22, 5834–5847 (2003). A comprehensive review that ties checkpoints induced by DNA damage to cell-cycle control, with particular emphasis on the roles of p53 and Cdc25.

    Article  CAS  PubMed  Google Scholar 

  17. Chow, J. P. H. et al. DNA damage during the spindle-assembly checkpoint degrades CDC25A, Inhibits Cyclin–CDC2 complexes, and reverses cells to interphase. Mol. Biol. Cell 14, 3989–4002 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xiao, Z. et al. Chk1 Mediates S and G2 Arrests through Cdc25A Degradation in Response to DNA-damaging Agents. J. Biol. Chem. 278, 21767–21773 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Boutros, R., Dozier, C. & Ducommun, B. The when and wheres of CDC25 phosphatases. Curr. Opin. Cell Biol. 18, 185–191 (2006). A recent review that emphasizes the complexity of Cdc25-mediated control of the cell cycle, including the role of protein localization and degradation.

    Article  CAS  PubMed  Google Scholar 

  20. Toogood, P. L. Progress toward the development of agents to modulate the cell cycle. Curr. Opin. Chem. Biol. 6, 472–478 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Kristjánsdóttir, K. & Rudolph, J. Cdc25 phosphatases and cancer. Chem. Biol. 11, 1043–1051 (2004).

    Article  PubMed  CAS  Google Scholar 

  22. Galaktionov, K. et al. Cdc25 phosphatases as potential human oncogenes. Science 269, 1575–1577 (1995). The first report to link Cdc25 overexpression to cancer, which opened the floodgates for further clinical studies and helped drive the interest of pharmaceutical companies towards targeting Cdc25s.

    Article  CAS  PubMed  Google Scholar 

  23. Galaktionov, K., Chen, X. & Beach, D. Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 382, 511–517 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Garner-Hamrick, P. A. & Fischer, C. Antisense phosphorothioate oligonucleotides specifically down-regulate cdc25B causing S-phase delay and persistant antiproliferative effects. Int. J. Cancer 76, 720–728 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Turowski, P. et al. Functional cdc25C dual-specificity phosphatase is required for S-phase entry in human cells. Mol. Biol. Cell 14, 2984–2998 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Blomberg, I. & Hoffmann, I. Ectopic expression of Cdc25A accelerates the G1/S transition and leads to premature activation of cyclin E- and cyclin A-dependent kinases. Mol. Cell. Biol. 19, 6183–6194 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gabrielli, B. G. et al. Cytoplasmic accumulation of cdc25B phosphatase in mitosis triggers centrosomal microtubule nucleation in HeLa cells. J. Cell Science 109, 1081–1093 (1996).

    CAS  PubMed  Google Scholar 

  28. Alonso, A. et al. Protein tyrosine phosphatases in the human genome. Cell 117, 699–711 (2004). A classification based on the sequence and structure of 107 different protein tyrosine phosphatases in the human genome, including their varying intracellular roles, modes of regulation and linkage to human diseases.

    Article  CAS  PubMed  Google Scholar 

  29. Robertson, J. G. Mechanistic basis of enzyme-target drugs. Biochemistry 44, 5561–5571 (2005). A comprehensive survey of 317 marketed drugs that inhibit 71 different enzymes, including details about the structural and mechanistic characteristics of these inhibitors.

    Article  CAS  PubMed  Google Scholar 

  30. Tonks, N. K. Protein tyrosine phosphatases: from genes, to function, to disease. Nature Rev. Mol. Cell Biol. 7, 833–846 (2006).

    Article  CAS  Google Scholar 

  31. Senderowicz, A. M. & Sausville, E. A. Preclinical and clinical development of cyclin-dependent kinase modulators. J. Natl Cancer Inst. 92, 376–387 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Prevost, G. P. et al. Inhibitors of the Cdc25 phosphatases. Prog. Cell Cycle Res. 5, 225–234 (2003). An excellent review including the structures and characteristics of a number of small-molecule inhibitors directed at the active sites of the Cdc25 phosphatases.

    PubMed  Google Scholar 

  33. Brisson, M. et al. Discovery and characterization of novel small molecule inhibitors of human Cdc25B dual specificity phosphatase. Mol. Pharmacol. 66, 824–833 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Hedstrom, L. Trypsin: a case study in the structural determinants of enzyme specificity. Biol. Chem. 377, 465–470 (1996).

    CAS  PubMed  Google Scholar 

  35. Songyang, Z. Recognition and regulation of primary-sequence motifs by signaling modular domains. Prog. Biophys. Mol. Biol. 71, 359–372 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Brown, N. R., Noble, M. E., Endicott, J. A. & Johnson, L. N. The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases. Nature Cell Biol. 1, 438–443 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Takeda, D. Y., Wohlschlegel, J. A. & Dutta, A. A bipartite substrate recognition motif for cyclin-dependent kinases. J. Biol. Chem. 276, 1993–1997 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Loog, M. & Morgan, D. O. Cyclin specificity in the phosphorylation of cyclin-dependent kinase substrates. Nature 434, 104–108 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Cheng, K.-Y. et al. The role of the phospho-CDK2/cyclin A recruitment site in substrate recognition. J. Biol. Chem. 281, 23167–23179 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Hartwell, L., Culottis, J. & Reid, B. Genetic control of the cell-division cycle in yeast, I. Detection of mutants. Proc. Natl Acad. Sci. USA 66, 352–359 (1970). This paper and subsequent papers by Lee Hartwell established the field of cell-cycle research using yeast as a model organism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Myers, M. P. et al. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J. Biol. Chem. 276, 47771–47774 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Ubersax, J. A. et al. Targets of the cyclin-dependent kinase Cdk1. Nature 425, 859–864 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Russell, P. & Nurse, P. cdc25+ functions as an inducer in the mitotic control of fission yeast. Cell 45, 145–153 (1986).

    Article  CAS  PubMed  Google Scholar 

  44. Gould, K. & Nurse, P. Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis. Nature 342, 39–45 (1989).

    Article  CAS  PubMed  Google Scholar 

  45. Kumagai, A. & Dunphy, W. G. The cdc25 protein controls tyrosine dephosphorylation of the cdc2 protein in a cell-free system. Cell 64, 903–914 (1991). The first study to show that Cdc25s are protein phosphatases.

    Article  CAS  PubMed  Google Scholar 

  46. Gautier, J., Solomon, M. J., Booher, R. N., Bazan, J. F. & Kirschner, M. W. Cdc25 is a specific tyrosine phosphatase that directly activates p34cdc2. Cell 67, 197–211 (1991).

    Article  CAS  PubMed  Google Scholar 

  47. Xu, X. & Burke, S. P. Roles of active site residues and the NH2-terminal domain in the catalysis and substrate binding of human Cdc25. J. Biol. Chem. 271, 5118–5124 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Rudolph, J., Epstein, D. M., Parker, L. & Eckstein, J. Specificity of natural and artificial substrates for human Cdc25A. Anal. Biochem. 289, 43–51 (2001). This work showed the importance of a protein–protein interaction in substrate recognition by the Cdc25s by comparing the activity of protein substrate with various peptidic substrates.

    Article  CAS  PubMed  Google Scholar 

  49. Wilborn, M., Free, S., Ban, A. & Rudolph, J. The C-terminal tail of the dual-specificity Cdc25B phosphatase mediates modular substrate recognition. Biochemistry 40, 14200–14206 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Janin, J. et al. CAPRI: A Critical Assessment of PRedicted Interactions. Proteins 52, 2–9 (2003). This summary heads an entire issue devoted to the development of new computational methods to predict protein docking.

    Article  CAS  PubMed  Google Scholar 

  51. Song, H. et al. Phosphoprotein-protein interactions revealed by the crystal structure of kinase-associated phosphatase in complex with phospho-Cdk2. Mol. Cell 7, 615–626 (2001). One of the few cases where the structure of a transient protein complex has been determined. Interestingly, as for CDC25B, the primary site of interaction is remote from the active site.

    Article  CAS  PubMed  Google Scholar 

  52. Tanoue, T. & Nishida, E. Molecular recognitions in the MAP kinase cascades. Cell Signal. 15, 455–462 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Chang, C. I., Xu, B. E., Akella, R., Cobb, M. H. & Goldsmith, E. J. Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b. Mol. Cell 9, 1241–1249 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Kim, H.-J., Park, J. E., Jin, S., Kim, J.-H. & Song, K. An isoquinolinium derivative selectively inhibits MAPK Spc1 of the stress-activated MAPK cascade of Schizosaccaromyces pombe. Chem. Biol. 13, 881–889 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Jeffrey, P. D. et al. Mechanism of CDK activation revealed by the structure of a CyclinA-CDK2 complex. Nature 376, 313–320 (1995).

    Article  CAS  PubMed  Google Scholar 

  56. Reynolds, R. A. et al. Crystal structure of the catalytic subunit of Cdc25B required for G2/M phase transition of the cell cycle. J. Mol. Biol. 293, 559–568 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Sohn, J. et al. Remote hotspots mediate protein substrate recognition for the Cdc25 phosphatase. Proc. Natl Acad. Sci. USA 47, 16437–16441 (2004).

    Article  CAS  Google Scholar 

  58. Sohn, J. et al. Experimental validation of the docking orientation of Cdc25 with its Cdk2/CycA protein substrate. Biochemistry 44, 16563–16573 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Sohn, J., Buhrman, G. & Rudolph, J. Kinetic and structural studies of specific protein-protein interactions in substrate catalysis by the Cdc25B phosphatase. Biochemistry 46, 807–818 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Atwell, S., Ultsch, M., DeVos, A. M. & Welss, J. A. Structural plasticity in a remodeled protein-protein interface. Science 278, 1125–1128 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Borgne, A. & Meijer, L. Sequential dephosphorylation of p34cdc2 on Thr-14 and Tyr-15 at the prophase/metaphase transition. J. Biol. Chem. 271, 27847–27854 (1996).

    Article  CAS  PubMed  Google Scholar 

  62. Ferrell, J. E. J. Xenopus oocyte maturation: new lessons from a good egg. Bioessays 21, 833–842 (1999).

    Article  PubMed  Google Scholar 

  63. Lee, M. S. et al. cdc25+ encodes a protein phosphatase that dephosphorylates p34cdc2. Mol. Biol. Cell 3, 73–84 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Russell, P., Moreno, S. & Reed, S. I. Conservation of mitotic controls in fission and budding yeast. Cell 57, 295–303 (1989).

    Article  CAS  PubMed  Google Scholar 

  65. Theesfeld, C. L., Zyla, T. R., Bardes, E. S. G. & Lew, D. J. A monitor for bud emergence in the yeast morphogenesis checkpoint. Mol. Biol. Cell 14, 3280–3291 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rutkoski, T. J., Kurten, E. L., Mitchell, J. C. & Raines, R. T. Disruption of shape-complementarity markers to create cytotoxic variants of ribonuclease A. J. Mol. Biol. 354, 41–54 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Berg, T. Modulation of protein-protein interactions with small organic molecules. Angew. Chem. Int. Ed. Engl. 42, 2462–2481 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Arkin, M. R. & Wells, J. A. Small-molecule inhibitors of protein-protein interactions: Progressing towards the dream. Nature Rev. Drug Discovery 3, 301–317 (2004). An excellent summary of recent significant developments for several inhibitors or protein–protein interactions, mainly directed at anticancer targets.

    Article  CAS  Google Scholar 

  69. Vassilev, L. T. et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844–848 (2004). Discovery, biochemical characterization and in vivo validation of a potent inhibitor of a protein–protein interaction.

    Article  CAS  PubMed  Google Scholar 

  70. Erlanson, D. A., Wells, J. A. & Braisted, A. C. Tethering: fragment-based drug discovery. Annu. Rev. Biophys. Biomol. Struct. 33, 199–223 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Shuker, S. B., Hajduk, P. J., Meadows, R. P. & Fesik, S. W. Discovering high-affinity ligands for proteins: SAR by NMR. Science 274, 1531–1534. (1996).

    Article  CAS  PubMed  Google Scholar 

  72. Uetz, P. et al. A comprehensive analysis of protein-protein interactions in Saccharomyces cerevisiae. Nature 403, 623–627 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Kamath, R. S., Martinez-Campos, M., Zipperlen, P., Fraser, A. G. & Ahrinnger, J. Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol. 2, RESEARCH0002 (2001).

  74. Ho, Y. et al. Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature 415, 180–183 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Lippincott-Schartz, J. & Patterson, G. H. Development and use of fluorescent protein markers in living cells. Science 300, 87–91 (2003).

    Article  CAS  Google Scholar 

  76. Takahashi, H., Nakanishi, T., Kami, K., Arata, Y. & Shimida, I. A novel NMR method for determing the interfaces of large protein-protein complexes. Nature Struct. Mol. Biol. 7, 220–223 (2000).

    Article  CAS  Google Scholar 

  77. Wrighton, N. C. et al. Small peptides as potent mimetics of the protein hormone erthyropoietin. Science 273, 458–463 (1996).

    Article  CAS  PubMed  Google Scholar 

  78. Fairbrother, W. J. et al. Novel peptides selected to bind vascular endothelial growth factor target the receptor-binding site. Biochemistry 37, 17754–17764 (1998).

    Article  CAS  PubMed  Google Scholar 

  79. Lowman, H. B. et al. Molecular mimics of insulin-like growth factor 1 (IGF-1) for inhibiting IGF-1: IGF-binding protein interactions. Biochemistry 37, 8870–8878 (1998).

    Article  CAS  PubMed  Google Scholar 

  80. Dédier, S., Reinelt, S., Rion, S., Folkers, G. & Rognan, D. Use of fluorescence polarization to monitor MHC-peptide interactions in solution. J. Immunol. Methods 255, 57–66 (2001).

    Article  PubMed  Google Scholar 

  81. Turek, T. C., Small, E. C., Bryant, R. W. & Hill, W. A. G. Development and validation of a competitive AKT serine/threonine kinase fluorescence polarization assay using a product-specific anti-phospho-serine antibody. Anal. Biochem. 299, 45–53 (2002).

    Article  CAS  Google Scholar 

  82. Kristjánsdóttir, K. & Rudolph, J. A fluorescence polarization assay for native protein substrates of kinases. Anal. Biochem. 316, 41–49 (2003).

    Article  PubMed  CAS  Google Scholar 

  83. Lo Conte, L., Chothia, C. & Janin, J. The atomic structure of protein-protein recognition sites. J. Mol. Biol. 285, 2177–2198 (1999). A statistical survey of protein–protein complexes that shows that the average interface buries 1,600 Å2 of solvent-exposed surface area and is composed of residues essentially indistinguishable from the remainder of the protein surface.

    Article  CAS  PubMed  Google Scholar 

  84. Clackson, T. & Wells, J. A. A hot spot of binding energy in a hormone-receptor interface. Science 267, 383–386 (1995).

    Article  CAS  PubMed  Google Scholar 

  85. Schreiber, S. & Fersht, A. R. Energetics of protein-protein interactions: analysis of the barnase-barstar interface by single mutations and double mutant cycles. J. Mol. Biol. 248, 478–486 (1995).

    CAS  PubMed  Google Scholar 

  86. Bogan, A. A. & Thorn, K. S. Anatomy of hot spots in protein interfaces. J. Mol. Biol. 280, 1–9 (1998). A survey of the characteristics of hotspot residues that finds an enrichment for arginine, tryptophan and tyrosine.

    Article  CAS  PubMed  Google Scholar 

  87. Agarwal, P. K., Edelsbrunner, H., Harer, J. & Wang, Y. Extreme elevation on a 2-manifold. Proc. 20th Ann. Sympos. Comput. Geom. 357–365 (2004). Describes the mathematical procedure by which one can find features such as 'mountains' and 'valleys' on a protein surface without the benefit of 'sea level' as a point of reference.

  88. Wang, Y., Agarwal, P. K., Edelsbrunner, H. & Rudolph, J. Coarse and reliable geometric alignment for protein docking. Pac. Symp. Biocomputing 64–75 (2005).

  89. Choi, V., Agarwal, P. K., Edelsbrunner, H. & Rudolph, J. Local search heuristic for rigid protein docking. 4th Workshop on Algorithms in Bioinformatics (WABI), Lecture Notes in Computer Science 3240, 218–229 (2004).

    Article  Google Scholar 

  90. Horovitz, A. Double-mutant cycles: a powerful tool for analyzing protein structure and function. Fold Design 1, R121–R126 (1996).

    Article  CAS  Google Scholar 

  91. Sohn, J. & Rudolph, J. The energetic network of hotspot residues between Cdc25B phosphatase and its protein substrate. J. Mol. Biol. 362, 1060–1071 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Nigg, E. A. Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle. BioEssays 17, 471–480 (1995).

    Article  CAS  PubMed  Google Scholar 

  93. Harper, J. W. & Elledge, S. J. The role of Cdk7 in CAK function, a retro-retrospective. Genes Dev. 12, 285–289 (1998).

    Article  CAS  PubMed  Google Scholar 

  94. Russo, A. A., Jeffrey, P. D. & Pavletich, N. P. Structural basis of cyclin-dependent kinase activation by phosphorylation. Nature Struct. Biol. 3, 696–700 (1996).

    Article  CAS  PubMed  Google Scholar 

  95. Morris, M. C., Gondeau, C., Tainer, J. A. & Divita, G. Kinetic mechanism of activation of the Cdk2/CyclinA complex. J. Bio. Chem. 277, 23847–23853 (2002).

    Article  CAS  Google Scholar 

  96. Hannon, G., Casso, D. & Beach, D. KAP: a DSP that interacts with cyclin-dependent kinases. Proc. Natl Acad. Sci. USA 91, 1731–1735 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Cangi, M. G. et al. Role of the Cdc25A phosphatase in human breast cancer. J. Clin. Invest. 106, 753–761 (2000). One of the most thorough and convincing studies linking Cdc25 overexpression to cancer and poor clinical outcome.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ito, Y. et al. Expression of cdc25A and cdc25B phosphatase in breast carcinoma. Breast Cancer 11, 295–300 (2004).

    Article  PubMed  Google Scholar 

  99. Takemara, I. et al. Overexpression of Cdc25B phosphatase as a novel marker of poor prognosis of human colorectal carcinoma. Cancer Res. 60, 3043–3050 (2000).

    Google Scholar 

  100. Hernández, S. et al. Differential expression of cdc25 cell-cycle-activating phosphatases in human colorectal carcinoma. Laboratory Invest. 81, 465–473 (2001).

    Article  Google Scholar 

  101. Wu, W. et al. Coordinate expression of Cdc25B and ER-α is frequent in low-grade endometrioid endometrial carcinoma but uncommon in high-grade endometrioid and nonendometrioid carcinomas. Cancer Res. 63, 6195–6199 (2003).

    CAS  PubMed  Google Scholar 

  102. Miyata, H. et al. Cdc25B and p53 are independently implicated in radiation sensitivity for human esophageal cancers. Clin. Cancer Res. 6, 4859–4865 (2000).

    CAS  PubMed  Google Scholar 

  103. Hu, Y. C., Lam, K. Y., Law, S., Wong, J. & Srivastava, G. Identification of differentially expressed genes in esophageal squamous cell carcinoma (ESCC) by cDNA expression array: overexpression of Fra-1, Neogenin, Id-1, and CDC25B genes in ESCC. Clin. Cancer Res. 7, 2213–2221 (2001).

    CAS  PubMed  Google Scholar 

  104. Nishioka, K. et al. Clinical significance of Cdc25A and Cdc25B expression in squamous cell carcinomas of the oesophagus. Br. J. Cancer 85, 412–421 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kudo, Y. et al. Overexpression of cyclin-dependent kinase-activating CDC25B phosphatase in human gastric carcinomas. Jap. J. Cancer Res. 88, 947–952 (1997).

    Article  CAS  Google Scholar 

  106. Nakabayashi, H., Hara, M. & Shimizu, K. Prognostic significance of Cdc25B expression in gliomas. J. Clin. Pathol. 59, 725–728 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Gasparotto, D. et al. Overexpression of Cdc25A and Cdc25B in head and neck cancers. Cancer Res. 57, 2366–2368 (1997).

    CAS  PubMed  Google Scholar 

  108. Xu, X. et al. Overexpression of CDC25A phosphatase is associated with hypergrowth activity and poor prognosis of human hepatocellular carcinomas. Clin. Cancer Res. 9, 1764–1772 (2003).

    CAS  PubMed  Google Scholar 

  109. Tang, L., Li, G., Tron, V. A., Trotter, M. J. & Ho, V. C. Expression of cell cycle regulators in human cutaneous malignant melanoma. Melanoma Res. 9, 148–154 (1999).

    Article  CAS  PubMed  Google Scholar 

  110. Sato, Y. et al. Expression of the cdc25B mRNA correlated with that of N-myc in neuroblastoma. Jpn J. Clin. Oncol. 31, 428–431 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Hernández, S. et al. Cdc25 cell cycle-activating phosphatases and c-myc expression in human non-Hodgkin's lymphomas. Cancer Res. 58, 1762–1767 (1998).

    PubMed  Google Scholar 

  112. Hernández, S. et al. Cdc25A and the splicing variant cdc25B2, but not cdc25B1, -B3 or-C, are over-expressed in aggressive human non-Hodgkin's lymphomas. Int. J. Cancer 89, 148–152 (2000).

    Article  PubMed  Google Scholar 

  113. Moreira Junior, G. et al. Reciprocal Cdc25A and p27 overexpression in B-cell non-Hodgkin lymphomas. Diagn. Mol. Pathol. 12, 128–132 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Wu, W., Fan, Y. H., Kemp, B. L., Walsh, G. & Mao, L. Overexpression of cdc25A and cdc25B is frequent in primary non-small cell lung cancer but is not associated with overexpression of c-myc. Cancer Res. 58, 4082–4085 (1998).

    CAS  PubMed  Google Scholar 

  115. Sasaki, H. et al. Expression of the cdc25B gene as a prognosis marker in non-small cell lung cancer. Cancer Lett. 173, 187–192 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Broggini, M. et al. Cell cycle-related phosphatases CDC25A and B expression correlates with survival in ovarian cancer patients. Anticancer Res. 20, 4835–4840 (2000).

    CAS  PubMed  Google Scholar 

  117. Guo, J. et al. Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma. Oncogene 23, 71–81 (2004).

    Article  PubMed  CAS  Google Scholar 

  118. Ngan, E. S. W., Hashimoto, Y., Ma, Z.-Q., Tsai, M. J. & Tsai, S. Y. Overexpression of Cdc25B, an androgen receptor coactivator, in prostate cancer. Oncogene 22, 734–739 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Ozen, M. & Ittmann, M. Increased expression and activity of CDC25C phosphatase and an alternatively spliced variant in prostate cancer. Clin. Cancer Res. 11, 4701–4706 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Ito, Y. et al. Expression of cdc25A and cdc25B proteins in thyroid neoplasms. Br. J. Cancer 86, 1909–1913 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ito, Y. et al. Cdc25A and cdc25B expression in malignant lymphoma of the thyroid: correlation with histological subtypes and cell proliferation. Int. J. Mol. Med. 13, 431–435 (2004).

    CAS  PubMed  Google Scholar 

  122. Ito, Y. et al. Expression of cdc25B and cdc25a in medullary thyroid carcinoma: cdc25B expression level predicts a poor prognosis. Cancer Lett. 229, 291–297 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Glossary

Active site

Typically, prominent cavities that contain specific amino acids for binding substrate and promoting catalysis.

Competitive inhibitor

An inhibitor that binds to the same site on a protein as the substrate, the concentration of which can be increased so as to overcome the inhibitory effect. Many competitive inhibitors have structures that resemble the substrate.

Docking site

A small fraction of a total protein surface, large compared to an active site, which mediates specific protein–protein associations.

Site-directed mutagenesis

The procedure by which one specifically replaces one or more amino acids with other amino acids. Often alanine serves as the replacement residue because of its small size and lack of functional groups.

Protein docking

The computational approach to predicting the orientation in which two proteins dock, starting with knowledge of their individual structures.

Interfacial contacts

The amino acids in the docking sites of interacting proteins that facilitate the specific formation and stabilization of a protein complex through their molecular interactions.

Plasticity

When the same residues on one specific protein use a molecularly diverse topology to form interfacial contacts with more than one other protein.

Genetic complementation

The reappearance of wild-type characteristics in an organism after the introduction of two simultaneous mutations, each of which alone is deleterious.

Hyphal

Normally growing yeast cells are essentially round. Hyphal cells are many times (2–10-fold) longer than they are wide.

Phage display

An in vitro selection technique using randomized sequences (typically 108–109) genetically fused to the outside surface of a phage virion to identify peptides with a chosen binding property.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rudolph, J. Inhibiting transient protein–protein interactions: lessons from the Cdc25 protein tyrosine phosphatases. Nat Rev Cancer 7, 202–211 (2007). https://doi.org/10.1038/nrc2087

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2087

This article is cited by

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