Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1998 Mar 2;17(5):1315–1327. doi: 10.1093/emboj/17.5.1315

The mitotic peptidyl-prolyl isomerase, Pin1, interacts with Cdc25 and Plx1.

D G Crenshaw 1, J Yang 1, A R Means 1, S Kornbluth 1
PMCID: PMC1170480  PMID: 9482729

Abstract

The cis/trans peptidyl-prolyl isomerase, Pin1, is a regulator of mitosis that is well conserved from yeast to man. Here we demonstrate that depletion of Pin1-binding proteins from Xenopus egg extracts results in hyperphosphorylation and inactivation of the key mitotic regulator, Cdc2/cyclin B. We show biochemically that this phenotype is a consequence of Pin1 interaction with critical upstream regulators of Cdc2/cyclin B, including the Cdc2-directed phosphatase, Cdc25, and its known regulator, Plx1. Although Pin1 could interact with Plx1 during interphase and mitosis, only the phosphorylated, mitotically active form of Cdc25 was able to bind Pin1, an event we have recapitulated using in vitro phosphorylated Cdc25. Taken together, these data suggest that Pin1 may modulate cell cycle control through interaction with Cdc25 and its activator, Plx1.

Full Text

The Full Text of this article is available as a PDF (482.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Atherton-Fessler S., Liu F., Gabrielli B., Lee M. S., Peng C. Y., Piwnica-Worms H. Cell cycle regulation of the p34cdc2 inhibitory kinases. Mol Biol Cell. 1994 Sep;5(9):989–1001. doi: 10.1091/mbc.5.9.989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bergen L. G., Upshall A., Morris N. R. S-phase, G2, and nuclear division mutants of Aspergillus nidulans. J Bacteriol. 1984 Jul;159(1):114–119. doi: 10.1128/jb.159.1.114-119.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Dasso M., Newport J. W. Completion of DNA replication is monitored by a feedback system that controls the initiation of mitosis in vitro: studies in Xenopus. Cell. 1990 Jun 1;61(5):811–823. doi: 10.1016/0092-8674(90)90191-g. [DOI] [PubMed] [Google Scholar]
  4. Davis F. M., Tsao T. Y., Fowler S. K., Rao P. N. Monoclonal antibodies to mitotic cells. Proc Natl Acad Sci U S A. 1983 May;80(10):2926–2930. doi: 10.1073/pnas.80.10.2926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dunphy W. G., Kumagai A. The cdc25 protein contains an intrinsic phosphatase activity. Cell. 1991 Oct 4;67(1):189–196. doi: 10.1016/0092-8674(91)90582-j. [DOI] [PubMed] [Google Scholar]
  6. Dunphy W. G. The decision to enter mitosis. Trends Cell Biol. 1994 Jun;4(6):202–207. doi: 10.1016/0962-8924(94)90142-2. [DOI] [PubMed] [Google Scholar]
  7. Furnari B., Rhind N., Russell P. Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint kinase. Science. 1997 Sep 5;277(5331):1495–1497. doi: 10.1126/science.277.5331.1495. [DOI] [PubMed] [Google Scholar]
  8. 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. 1991 Oct 4;67(1):197–211. doi: 10.1016/0092-8674(91)90583-k. [DOI] [PubMed] [Google Scholar]
  9. Golsteyn R. M., Mundt K. E., Fry A. M., Nigg E. A. Cell cycle regulation of the activity and subcellular localization of Plk1, a human protein kinase implicated in mitotic spindle function. J Cell Biol. 1995 Jun;129(6):1617–1628. doi: 10.1083/jcb.129.6.1617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hamanaka R., Smith M. R., O'Connor P. M., Maloid S., Mihalic K., Spivak J. L., Longo D. L., Ferris D. K. Polo-like kinase is a cell cycle-regulated kinase activated during mitosis. J Biol Chem. 1995 Sep 8;270(36):21086–21091. doi: 10.1074/jbc.270.36.21086. [DOI] [PubMed] [Google Scholar]
  11. Hanes S. D., Shank P. R., Bostian K. A. Sequence and mutational analysis of ESS1, a gene essential for growth in Saccharomyces cerevisiae. Yeast. 1989 Jan-Feb;5(1):55–72. doi: 10.1002/yea.320050108. [DOI] [PubMed] [Google Scholar]
  12. Izumi T., Maller J. L. Phosphorylation and activation of the Xenopus Cdc25 phosphatase in the absence of Cdc2 and Cdk2 kinase activity. Mol Biol Cell. 1995 Feb;6(2):215–226. doi: 10.1091/mbc.6.2.215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kornbluth S., Sebastian B., Hunter T., Newport J. Membrane localization of the kinase which phosphorylates p34cdc2 on threonine 14. Mol Biol Cell. 1994 Mar;5(3):273–282. doi: 10.1091/mbc.5.3.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Krek W., Marks J., Schmitz N., Nigg E. A., Simanis V. Vertebrate p34cdc2 phosphorylation site mutants: effects upon cell cycle progression in the fission yeast Schizosaccharomyces pombe. J Cell Sci. 1992 May;102(Pt 1):43–53. doi: 10.1242/jcs.102.1.43. [DOI] [PubMed] [Google Scholar]
  15. Kumagai A., Dunphy W. G. Purification and molecular cloning of Plx1, a Cdc25-regulatory kinase from Xenopus egg extracts. Science. 1996 Sep 6;273(5280):1377–1380. doi: 10.1126/science.273.5280.1377. [DOI] [PubMed] [Google Scholar]
  16. Kumagai A., Dunphy W. G. Regulation of the cdc25 protein during the cell cycle in Xenopus extracts. Cell. 1992 Jul 10;70(1):139–151. doi: 10.1016/0092-8674(92)90540-s. [DOI] [PubMed] [Google Scholar]
  17. Lane H. A., Nigg E. A. Antibody microinjection reveals an essential role for human polo-like kinase 1 (Plk1) in the functional maturation of mitotic centrosomes. J Cell Biol. 1996 Dec;135(6 Pt 2):1701–1713. doi: 10.1083/jcb.135.6.1701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lee K. S., Yuan Y. L., Kuriyama R., Erikson R. L. Plk is an M-phase-specific protein kinase and interacts with a kinesin-like protein, CHO1/MKLP-1. Mol Cell Biol. 1995 Dec;15(12):7143–7151. doi: 10.1128/mcb.15.12.7143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Liu F., Stanton J. J., Wu Z., Piwnica-Worms H. The human Myt1 kinase preferentially phosphorylates Cdc2 on threonine 14 and localizes to the endoplasmic reticulum and Golgi complex. Mol Cell Biol. 1997 Feb;17(2):571–583. doi: 10.1128/mcb.17.2.571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lu K. P., Hanes S. D., Hunter T. A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature. 1996 Apr 11;380(6574):544–547. doi: 10.1038/380544a0. [DOI] [PubMed] [Google Scholar]
  21. Lu K. P., Osmani S. A., Means A. R. Properties and regulation of the cell cycle-specific NIMA protein kinase of Aspergillus nidulans. J Biol Chem. 1993 Apr 25;268(12):8769–8776. [PubMed] [Google Scholar]
  22. Maleszka R., Hanes S. D., Hackett R. L., de Couet H. G., Miklos G. L. The Drosophila melanogaster dodo (dod) gene, conserved in humans, is functionally interchangeable with the ESS1 cell division gene of Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):447–451. doi: 10.1073/pnas.93.1.447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. McGowan C. H., Russell P. Cell cycle regulation of human WEE1. EMBO J. 1995 May 15;14(10):2166–2175. doi: 10.1002/j.1460-2075.1995.tb07210.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Millar J. B., Russell P. The cdc25 M-phase inducer: an unconventional protein phosphatase. Cell. 1992 Feb 7;68(3):407–410. doi: 10.1016/0092-8674(92)90177-e. [DOI] [PubMed] [Google Scholar]
  25. Morris N. R. Mitotic mutants of Aspergillus nidulans. Genet Res. 1975 Dec;26(3):237–254. doi: 10.1017/s0016672300016049. [DOI] [PubMed] [Google Scholar]
  26. Mueller P. R., Coleman T. R., Dunphy W. G. Cell cycle regulation of a Xenopus Wee1-like kinase. Mol Biol Cell. 1995 Jan;6(1):119–134. doi: 10.1091/mbc.6.1.119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Mueller P. R., Coleman T. R., Kumagai A., Dunphy W. G. Myt1: a membrane-associated inhibitory kinase that phosphorylates Cdc2 on both threonine-14 and tyrosine-15. Science. 1995 Oct 6;270(5233):86–90. doi: 10.1126/science.270.5233.86. [DOI] [PubMed] [Google Scholar]
  28. Murray A. W., Kirschner M. W. Cyclin synthesis drives the early embryonic cell cycle. Nature. 1989 May 25;339(6222):275–280. doi: 10.1038/339275a0. [DOI] [PubMed] [Google Scholar]
  29. Murray A. W., Solomon M. J., Kirschner M. W. The role of cyclin synthesis and degradation in the control of maturation promoting factor activity. Nature. 1989 May 25;339(6222):280–286. doi: 10.1038/339280a0. [DOI] [PubMed] [Google Scholar]
  30. Norbury C., Blow J., Nurse P. Regulatory phosphorylation of the p34cdc2 protein kinase in vertebrates. EMBO J. 1991 Nov;10(11):3321–3329. doi: 10.1002/j.1460-2075.1991.tb04896.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Nurse P. Universal control mechanism regulating onset of M-phase. Nature. 1990 Apr 5;344(6266):503–508. doi: 10.1038/344503a0. [DOI] [PubMed] [Google Scholar]
  32. Osmani A. H., McGuire S. L., Osmani S. A. Parallel activation of the NIMA and p34cdc2 cell cycle-regulated protein kinases is required to initiate mitosis in A. nidulans. Cell. 1991 Oct 18;67(2):283–291. doi: 10.1016/0092-8674(91)90180-7. [DOI] [PubMed] [Google Scholar]
  33. Osmani A. H., O'Donnell K., Pu R. T., Osmani S. A. Activation of the nimA protein kinase plays a unique role during mitosis that cannot be bypassed by absence of the bimE checkpoint. EMBO J. 1991 Sep;10(9):2669–2679. doi: 10.1002/j.1460-2075.1991.tb07810.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Osmani S. A., May G. S., Morris N. R. Regulation of the mRNA levels of nimA, a gene required for the G2-M transition in Aspergillus nidulans. J Cell Biol. 1987 Jun;104(6):1495–1504. doi: 10.1083/jcb.104.6.1495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Osmani S. A., Pu R. T., Morris N. R. Mitotic induction and maintenance by overexpression of a G2-specific gene that encodes a potential protein kinase. Cell. 1988 Apr 22;53(2):237–244. doi: 10.1016/0092-8674(88)90385-6. [DOI] [PubMed] [Google Scholar]
  36. Peng C. Y., Graves P. R., Thoma R. S., Wu Z., Shaw A. S., Piwnica-Worms H. Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science. 1997 Sep 5;277(5331):1501–1505. doi: 10.1126/science.277.5331.1501. [DOI] [PubMed] [Google Scholar]
  37. Rahfeld J. U., Rücknagel K. P., Schelbert B., Ludwig B., Hacker J., Mann K., Fischer G. Confirmation of the existence of a third family among peptidyl-prolyl cis/trans isomerases. Amino acid sequence and recombinant production of parvulin. FEBS Lett. 1994 Sep 26;352(2):180–184. doi: 10.1016/0014-5793(94)00932-5. [DOI] [PubMed] [Google Scholar]
  38. Ranganathan R., Lu K. P., Hunter T., Noel J. P. Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent. Cell. 1997 Jun 13;89(6):875–886. doi: 10.1016/s0092-8674(00)80273-1. [DOI] [PubMed] [Google Scholar]
  39. Sanchez Y., Wong C., Thoma R. S., Richman R., Wu Z., Piwnica-Worms H., Elledge S. J. Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science. 1997 Sep 5;277(5331):1497–1501. doi: 10.1126/science.277.5331.1497. [DOI] [PubMed] [Google Scholar]
  40. Schmid F. X. Protein folding. Prolyl isomerases join the fold. Curr Biol. 1995 Sep 1;5(9):993–994. doi: 10.1016/s0960-9822(95)00197-7. [DOI] [PubMed] [Google Scholar]
  41. Smythe C., Newport J. W. Coupling of mitosis to the completion of S phase in Xenopus occurs via modulation of the tyrosine kinase that phosphorylates p34cdc2. Cell. 1992 Feb 21;68(4):787–797. doi: 10.1016/0092-8674(92)90153-4. [DOI] [PubMed] [Google Scholar]
  42. Smythe C., Newport J. W. Systems for the study of nuclear assembly, DNA replication, and nuclear breakdown in Xenopus laevis egg extracts. Methods Cell Biol. 1991;35:449–468. doi: 10.1016/s0091-679x(08)60583-x. [DOI] [PubMed] [Google Scholar]
  43. Solomon M. J. Activation of the various cyclin/cdc2 protein kinases. Curr Opin Cell Biol. 1993 Apr;5(2):180–186. doi: 10.1016/0955-0674(93)90100-5. [DOI] [PubMed] [Google Scholar]
  44. Solomon M. J., Glotzer M., Lee T. H., Philippe M., Kirschner M. W. Cyclin activation of p34cdc2. Cell. 1990 Nov 30;63(5):1013–1024. doi: 10.1016/0092-8674(90)90504-8. [DOI] [PubMed] [Google Scholar]
  45. Solomon M. J., Lee T., Kirschner M. W. Role of phosphorylation in p34cdc2 activation: identification of an activating kinase. Mol Biol Cell. 1992 Jan;3(1):13–27. doi: 10.1091/mbc.3.1.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Strausfeld U., Labbé J. C., Fesquet D., Cavadore J. C., Picard A., Sadhu K., Russell P., Dorée M. Dephosphorylation and activation of a p34cdc2/cyclin B complex in vitro by human CDC25 protein. Nature. 1991 May 16;351(6323):242–245. doi: 10.1038/351242a0. [DOI] [PubMed] [Google Scholar]
  47. Sudol M. Structure and function of the WW domain. Prog Biophys Mol Biol. 1996;65(1-2):113–132. doi: 10.1016/s0079-6107(96)00008-9. [DOI] [PubMed] [Google Scholar]
  48. Watanabe N., Broome M., Hunter T. Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle. EMBO J. 1995 May 1;14(9):1878–1891. doi: 10.1002/j.1460-2075.1995.tb07180.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Yaffe M. B., Schutkowski M., Shen M., Zhou X. Z., Stukenberg P. T., Rahfeld J. U., Xu J., Kuang J., Kirschner M. W., Fischer G. Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism. Science. 1997 Dec 12;278(5345):1957–1960. doi: 10.1126/science.278.5345.1957. [DOI] [PubMed] [Google Scholar]
  50. Ye X. S., Xu G., Pu R. T., Fincher R. R., McGuire S. L., Osmani A. H., Osmani S. A. The NIMA protein kinase is hyperphosphorylated and activated downstream of p34cdc2/cyclin B: coordination of two mitosis promoting kinases. EMBO J. 1995 Mar 1;14(5):986–994. doi: 10.1002/j.1460-2075.1995.tb07079.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES