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.

Plk1 regulates contraction of postmitotic smooth muscle cells and is required for vascular homeostasis

Abstract

Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo. Mechanistically, we found that Plk1 regulated angiotensin II–dependent activation of RhoA and actomyosin dynamics in VSMCs in a mitosis-independent manner. This regulation depended on Plk1 kinase activity, and the administration of small-molecule Plk1 inhibitors to angiotensin II–treated mice led to reduced arterial fitness and an elevated risk of aneurysm and aortic rupture. We thus conclude that a partial reduction of Plk1 activity that does not block cell division can nevertheless impair aortic homeostasis. Our findings have potentially important implications for current approaches aimed at PLK1 inhibition for cancer therapy.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Genetic ablation of Plk1 in adult mice.
Figure 2: Plk1 function in VSMCs in vivo.
Figure 3: Plk1 modulates the RhoA pathway in interphase VSMCs.
Figure 4: Plk1 modulates activation of the RhoA pathway by Ect2.
Figure 5: Dynamic relocalization of Plk1 and Ect2, and its control by aPKC.
Figure 6: Plk1 inhibition impairs vascular homeostasis in vivo.

References

  1. 1

    Llamazares, S. et al. polo encodes a protein kinase homolog required for mitosis in Drosophila. Genes Dev. 5, 2153–2165 (1991).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Sunkel, C.E. & Glover, D.M. polo, a mitotic mutant of Drosophila displaying abnormal spindle poles. J. Cell Sci. 89, 25–38 (1988).

    PubMed  Google Scholar 

  3. 3

    Barr, F.A., Silljé, H.H. & Nigg, E.A. Polo-like kinases and the orchestration of cell division. Nat. Rev. Mol. Cell Biol. 5, 429–440 (2004).

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Lens, S.M., Voest, E.E. & Medema, R.H. Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat. Rev. Cancer 10, 825–841 (2010).

    CAS  PubMed  Article  Google Scholar 

  5. 5

    Archambault, V. & Glover, D.M. Polo-like kinases: conservation and divergence in their functions and regulation. Nat. Rev. Mol. Cell Biol. 10, 265–275 (2009).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Petronczki, M., Lénárt, P. & Peters, J.M. Polo on the rise—from mitotic entry to cytokinesis with Plk1. Dev. Cell 14, 646–659 (2008).

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Taylor, S. & Peters, J.M. Polo and Aurora kinases: lessons derived from chemical biology. Curr. Opin. Cell Biol. 20, 77–84 (2008).

    CAS  PubMed  Article  Google Scholar 

  8. 8

    Strebhardt, K. & Ullrich, A. Targeting polo-like kinase 1 for cancer therapy. Nat. Rev. Cancer 6, 321–330 (2006).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    McInnes, C. & Wyatt, M.D. PLK1 as an oncology target: current status and future potential. Drug Discov. Today 16, 619–625 (2011).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Döhner, H. et al. Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy. Blood 124, 1426–1433 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11

    Gjertsen, B.T. & Schöffski, P. Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy. Leukemia 29, 11–19 (2015).

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Lu, L.Y. et al. Polo-like kinase 1 is essential for early embryonic development and tumor suppression. Mol. Cell. Biol. 28, 6870–6876 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13

    Wachowicz, P., Fernández-Miranda, G., Marugán, C., Escobar, B. & de Cárcer, G. Genetic depletion of Polo-like kinase 1 leads to embryonic lethality due to mitotic aberrancies. BioEssays 38, S96–S106 (2016).

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Trakala, M. et al. Activation of the endomitotic spindle assembly checkpoint and thrombocytopenia in Plk1-deficient mice. Blood 126, 1707–1714 (2015).

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Guerra, C. et al. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4, 111–120 (2003).

    CAS  Article  Google Scholar 

  16. 16

    Winkles, J.A. & Alberts, G.F. Differential regulation of polo-like kinase 1, 2, 3, and 4 gene expression in mammalian cells and tissues. Oncogene 24, 260–266 (2005).

    CAS  PubMed  Article  Google Scholar 

  17. 17

    Kühbandner, S. et al. Temporally controlled somatic mutagenesis in smooth muscle. Genesis 28, 15–22 (2000).

    PubMed  Article  Google Scholar 

  18. 18

    Loirand, G. & Pacaud, P. Involvement of Rho GTPases and their regulators in the pathogenesis of hypertension. Small GTPases 5, 1–10 (2014).

    PubMed  Article  CAS  Google Scholar 

  19. 19

    Guilluy, C. et al. The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure. Nat. Med. 16, 183–190 (2010).

    CAS  PubMed  Article  Google Scholar 

  20. 20

    Wirth, A. et al. G12-G13-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension. Nat. Med. 14, 64–68 (2008).

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Wuertz, C.M. et al. p63RhoGEF—a key mediator of angiotensin II-dependent signaling and processes in vascular smooth muscle cells. FASEB J. 24, 4865–4876 (2010).

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Ying, Z., Giachini, F.R., Tostes, R.C. & Webb, R.C. PYK2/PDZ-RhoGEF links Ca2+ signaling to RhoA. Arterioscler. Thromb. Vasc. Biol. 29, 1657–1663 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Zhao, W.M. & Fang, G. MgcRacGAP controls the assembly of the contractile ring and the initiation of cytokinesis. Proc. Natl. Acad. Sci. USA 102, 13158–13163 (2005).

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Petronczki, M., Glotzer, M., Kraut, N. & Peters, J.M. Polo-like kinase 1 triggers the initiation of cytokinesis in human cells by promoting recruitment of the RhoGEF Ect2 to the central spindle. Dev. Cell 12, 713–725 (2007).

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Burkard, M.E. et al. Plk1 self-organization and priming phosphorylation of HsCYK-4 at the spindle midzone regulate the onset of division in human cells. PLoS Biol. 7, e1000111 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. 26

    Wolfe, B.A., Takaki, T., Petronczki, M. & Glotzer, M. Polo-like kinase 1 directs assembly of the HsCyk-4 RhoGAP/Ect2 RhoGEF complex to initiate cleavage furrow formation. PLoS Biol. 7, e1000110 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. 27

    Zhang, D. & Glotzer, M. The RhoGAP activity of CYK-4/MgcRacGAP functions non-canonically by promoting RhoA activation during cytokinesis. eLife 4, e08898 (2015).

    PubMed Central  Article  PubMed  Google Scholar 

  28. 28

    Hirose, K., Kawashima, T., Iwamoto, I., Nosaka, T. & Kitamura, T. MgcRacGAP is involved in cytokinesis through associating with mitotic spindle and midbody. J. Biol. Chem. 276, 5821–5828 (2001).

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Ratheesh, A. et al. Centralspindlin and α-catenin regulate Rho signalling at the epithelial zonula adherens. Nat. Cell Biol. 14, 818–828 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Niiya, F., Tatsumoto, T., Lee, K.S. & Miki, T. Phosphorylation of the cytokinesis regulator ECT2 at G2/M phase stimulates association of the mitotic kinase Plk1 and accumulation of GTP-bound RhoA. Oncogene 25, 827–837 (2006).

    CAS  PubMed  Article  Google Scholar 

  31. 31

    Hara, T. et al. Cytokinesis regulator ECT2 changes its conformation through phosphorylation at Thr-341 in G2/M phase. Oncogene 25, 566–578 (2006).

    CAS  PubMed  Article  Google Scholar 

  32. 32

    Justilien, V., Jameison, L., Der, C.J., Rossman, K.L. & Fields, A.P. Oncogenic activity of Ect2 is regulated through protein kinase Cι-mediated phosphorylation. J. Biol. Chem. 286, 8149–8157 (2011).

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Yoshida, S. et al. Polo-like kinase Cdc5 controls the local activation of Rho1 to promote cytokinesis. Science 313, 108–111 (2006).

    CAS  PubMed  Article  Google Scholar 

  34. 34

    Ohkura, H., Hagan, I.M. & Glover, D.M. The conserved Schizosaccharomyces pombe kinase plo1, required to form a bipolar spindle, the actin ring, and septum, can drive septum formation in G1 and G2 cells. Genes Dev. 9, 1059–1073 (1995).

    CAS  PubMed  Article  Google Scholar 

  35. 35

    Petersen, J. & Hagan, I.M. Polo kinase links the stress pathway to cell cycle control and tip growth in fission yeast. Nature 435, 507–512 (2005).

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Guilluy, C., Garcia-Mata, R. & Burridge, K. Rho protein crosstalk: another social network? Trends Cell Biol. 21, 718–726 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37

    Cario-Toumaniantz, C. et al. RhoA guanine exchange factor expression profile in arteries: evidence for a Rho kinase-dependent negative feedback in angiotensin II-dependent hypertension. Am. J. Physiol. Cell Physiol. 302, C1394–C1404 (2012).

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Liu, X.F., Ishida, H., Raziuddin, R. & Miki, T. Nucleotide exchange factor ECT2 interacts with the polarity protein complex Par6/Par3/protein kinase Cζ (PKCζ) and regulates PKCζ activity. Mol. Cell. Biol. 24, 6665–6675 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Justilien, V. & Fields, A.P. Ect2 links the PKCι-Par6α complex to Rac1 activation and cellular transformation. Oncogene 28, 3597–3607 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    Matthews, H.K. et al. Changes in Ect2 localization couple actomyosin-dependent cell shape changes to mitotic progression. Dev. Cell 23, 371–383 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41

    Suzuki, K. et al. Identification of non-Ser/Thr-Pro consensus motifs for Cdk1 and their roles in mitotic regulation of C2H2 zinc finger proteins and Ect2. Sci. Rep. 5, 7929 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42

    Liao, D.F., Monia, B., Dean, N. & Berk, B.C. Protein kinase C-ζ mediates angiotensin II activation of ERK1/2 in vascular smooth muscle cells. J. Biol. Chem. 272, 6146–6150 (1997).

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Pan, J. et al. PKC mediates cyclic stretch-induced cardiac hypertrophy through Rho family GTPases and mitogen-activated protein kinases in cardiomyocytes. J. Cell. Physiol. 202, 536–553 (2005).

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Lindsay, M.E. & Dietz, H.C. The genetic basis of aortic aneurysm. Cold Spring Harb. Perspect. Med. 4, a015909 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45

    Milewicz, D.M., Regalado, E.S., Shendure, J., Nickerson, D.A. & Guo, D.C. Successes and challenges of using whole exome sequencing to identify novel genes underlying an inherited predisposition for thoracic aortic aneurysms and acute aortic dissections. Trends Cardiovasc. Med. 24, 53–60 (2014).

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Zhu, L. et al. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat. Genet. 38, 343–349 (2006).

    CAS  PubMed  Article  Google Scholar 

  47. 47

    Wang, L. et al. Mutations in myosin light chain kinase cause familial aortic dissections. Am. J. Hum. Genet. 87, 701–707 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48

    Kuang, S.Q. et al. Rare, nonsynonymous variant in the smooth muscle-specific isoform of myosin heavy chain, MYH11, R247C, alters force generation in the aorta and phenotype of smooth muscle cells. Circ. Res. 110, 1411–1422 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49

    Bellini, C., Wang, S., Milewicz, D.M. & Humphrey, J.D. Myh11(R247C/R247C) mutations increase thoracic aorta vulnerability to intramural damage despite a general biomechanical adaptivity. J. Biomech. 48, 113–121 (2015).

    PubMed  Article  Google Scholar 

  50. 50

    He, W.Q. et al. Myosin light chain kinase is central to smooth muscle contraction and required for gastrointestinal motility in mice. Gastroenterology 135, 610–620 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51

    He, W.Q. et al. Altered contractile phenotypes of intestinal smooth muscle in mice deficient in myosin phosphatase target subunit 1. Gastroenterology 144, 1456–1465 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52

    Yamashiro, S. et al. Myosin phosphatase-targeting subunit 1 regulates mitosis by antagonizing polo-like kinase 1. Dev. Cell 14, 787–797 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53

    Li, J. et al. Polo-like kinase 1 regulates vimentin phosphorylation at Ser-56 and contraction in smooth muscle. J. Biol. Chem. 291, 23693–23703 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54

    Gutteridge, R.E., Ndiaye, M.A., Liu, X. & Ahmad, N. Plk1 inhibitors in cancer therapy: from laboratory to clinics. Mol. Cancer Ther. 15, 1427–1435 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55

    Olmos, D. et al. Phase I study of GSK461364, a specific and competitive Polo-like kinase 1 inhibitor, in patients with advanced solid malignancies. Clin. Cancer Res. 17, 3420–3430 (2011).

    CAS  PubMed  Article  Google Scholar 

  56. 56

    Sebastian, M. et al. The efficacy and safety of BI 2536, a novel Plk-1 inhibitor, in patients with stage IIIB/IV non-small cell lung cancer who had relapsed after, or failed, chemotherapy: results from an open-label, randomized phase II clinical trial. J. Thorac. Oncol. 5, 1060–1067 (2010).

    PubMed  Article  Google Scholar 

  57. 57

    Hofheinz, R.D. et al. An open-label, phase I study of the polo-like kinase-1 inhibitor, BI 2536, in patients with advanced solid tumors. Clin. Cancer Res. 16, 4666–4674 (2010).

    CAS  PubMed  Article  Google Scholar 

  58. 58

    Komrokji, R.S. et al. Phase I clinical trial of oral rigosertib in patients with myelodysplastic syndromes. Br. J. Haematol. 162, 517–524 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59

    Vega, F.M. & Ridley, A.J. Rho GTPases in cancer cell biology. FEBS Lett. 582, 2093–2101 (2008).

    CAS  PubMed  Article  Google Scholar 

  60. 60

    Mardilovich, K., Olson, M.F. & Baugh, M. Targeting Rho GTPase signaling for cancer therapy. Future Oncol. 8, 165–177 (2012).

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Rudolph, D. et al. BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin. Cancer Res. 15, 3094–3102 (2009).

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Ray, J.L., Leach, R., Herbert, J.M. & Benson, M. Isolation of vascular smooth muscle cells from a single murine aorta. Methods Cell Sci. 23, 185–188 (2001).

    CAS  PubMed  Article  Google Scholar 

  63. 63

    Jat, P.S. et al. Direct derivation of conditionally immortal cell lines from an H-2Kb-tsA58 transgenic mouse. Proc. Natl. Acad. Sci. USA 88, 5096–5100 (1991).

    CAS  PubMed  Article  Google Scholar 

  64. 64

    Caloca, M.J., Zugaza, J.L., Matallanas, D., Crespo, P. & Bustelo, X.R. Vav mediates Ras stimulation by direct activation of the GDP/GTP exchange factor Ras GRP1. EMBO J. 22, 3326–3336 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65

    Ren, X.D. et al. Disruption of Rho signal transduction upon cell detachment. J. Cell Sci. 117, 3511–3518 (2004).

    CAS  PubMed  Article  Google Scholar 

  66. 66

    Grande-García, A. et al. Caveolin-1 regulates cell polarization and directional migration through Src kinase and Rho GTPases. J. Cell Biol. 177, 683–694 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. 67

    Reuther, G.W. et al. Leukemia-associated Rho guanine nucleotide exchange factor, a Dbl family protein found mutated in leukemia, causes transformation by activation of RhoA. J. Biol. Chem. 276, 27145–27151 (2001).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Ren, X.D., Kiosses, W.B. & Schwartz, M.A. Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskeleton. EMBO J. 18, 578–585 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    Waheed, F., Speight, P., Dan, Q., Garcia-Mata, R. & Szaszi, K. Affinity precipitation of active Rho-GEFs using a GST-tagged mutant Rho protein (GST-RhoA(G17A)) from epithelial cell lysates. J. Vis. Exp. 61, e3932 (2012).

    Google Scholar 

  70. 70

    Dubash, A.D. et al. A novel role for Lsc/p115 RhoGEF and LARG in regulating RhoA activity downstream of adhesion to fibronectin. J. Cell Sci. 120, 3989–3998 (2007).

    CAS  PubMed  Article  Google Scholar 

  71. 71

    de Cárcer, G. et al. Plk5, a polo box domain-only protein with specific roles in neuron differentiation and glioblastoma suppression. Mol. Cell. Biol. 31, 1225–1239 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

Acknowledgements

We are fully indebted to K. Burridge (The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA), C.J. Der (The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA), A.P. Fields (Mayo Clinic, Jacksonville, Florida, USA), M. Glotzer (University of Chicago, Chicago, Illinois, USA), M. Angel del Pozo (CNIC, Madrid, Spain) and M. Yaffe (The Koch Institute, MIT, Cambridge, Massachusetts, USA) for reagents. We thank A. Borgia for help with biochemical studies; the ultrasonographers A.V. Alonso and L. Flores; A. Peral and R. Alberca for technical assistance; J. Regadera for advice on mouse echocardiography and pathological samples; and members of the Histopathology and Transgenic Units of the CNIO for excellent technical support. We also thank D. Olmos for discussion on the effect of Plk1 inhibitors in the clinic. This work was supported by the Marie Curie activities of the European Commission (Oncotrain program; fellowship to P.W.), the Spanish Ministry of Economy and Competitiveness (MINECO; fellowship to A.G.-L.), the CENIT AMIT Project “Advanced Molecular Imaging Technologies” (TEC2008-06715-C02-1, RD07/0014/2009 to F.M.), the Red de Investigación Cardiovascular (RIC), cofunded by FEDER (grant RD12/0042/0022 to J.M.R.; grant RD12/0042/0056 to L.J.J.-B.), Fundació La Marató TV3 (grant 20151331 to J.M.R.), the Castilla-León Autonomous Government (BIO/SA01/15, CS049U16 to X.R.B.), the Solórzano and Ramón Areces Foundations (to X.R.B.), MINECO (grants RD12/0036/0002 and SAF2015-64556-R to X.R.B.; SAF2015-63633-R to J.M.R.; and SAF2015-69920-R to M.M.), Consolider-Ingenio 2010 Programme (grant SAF2014-57791-REDC to M.M.), Red Temática CellSYS (grant BFU2014-52125-REDT to M.M.), Comunidad de Madrid (OncoCycle Programme; grant S2010/BMD-2470 to M.M.), Worldwide Cancer Research (grants 14-1248 to X.R.B., and 15-0278 to M.M.) and the MitoSys project (European Union Seventh Framework Programme; grant HEALTH-F5-2010-241548 to M.M.). CNIC is supported by MINECO and the Pro-CNIC Foundation. CNIO and CNIC are Severo Ochoa Centers of Excellence (MINECO awards SEV-2015-0510 and SEV-2015-0505, respectively).

Author information

Affiliations

Authors

Contributions

G.d.C. performed most of the cellular and mouse experiments, with technical support from B.E. and A.E.B. P.W. generated the Plk1 alleles and performed initial experiments in Plk1 heterozygous mice and VSMCs. S.M.-M., J.O., N.M.-B., L.J.J.-B. and J.M.R. provided intellectual input on the cardiovascular studies and contributed to the phenotypic analysis of the vascular phenotype in mice. A.G.-L. helped with cellular and biochemical assays. J.A.C. and F.M. helped with echocardiography measurements. M.J.M. and M.d.l.A.S. performed the contractility and elasticity assays in the rings from aortas or the mesenteric arteries. X.R.B. provided intellectual input for the initial project design and further troubleshooting. T.T. studied the phosphorylation of Ect2 by Plk1. M.C. performed the histopathological analysis. G.d.C. and M.M. supervised the project and wrote the manuscript with the help of all other authors.

Corresponding authors

Correspondence to Guillermo de Cárcer or Juan Miguel Redondo or Marcos Malumbres.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures and Tables

Supplementary Figures 1–11 and Supplementary Tables 1–4 (PDF 5354 kb)

Reporting Summary

Life Sciences Reporting Summary (PDF 162 kb)

Source data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

de Cárcer, G., Wachowicz, P., Martínez-Martínez, S. et al. Plk1 regulates contraction of postmitotic smooth muscle cells and is required for vascular homeostasis. Nat Med 23, 964–974 (2017). https://doi.org/10.1038/nm.4364

Download citation

Further reading

  • Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma

    • Chen Huang
    • , Lijun Chen
    • , Sara R. Savage
    • , Rodrigo Vargas Eguez
    • , Yongchao Dou
    • , Yize Li
    • , Felipe da Veiga Leprevost
    • , Eric J. Jaehnig
    • , Jonathan T. Lei
    • , Bo Wen
    • , Michael Schnaubelt
    • , Karsten Krug
    • , Xiaoyu Song
    • , Marcin Cieślik
    • , Hui-Yin Chang
    • , Matthew A. Wyczalkowski
    • , Kai Li
    • , Antonio Colaprico
    • , Qing Kay Li
    • , David J. Clark
    • , Yingwei Hu
    • , Liwei Cao
    • , Jianbo Pan
    • , Yuefan Wang
    • , Kyung-Cho Cho
    • , Zhiao Shi
    • , Yuxing Liao
    • , Wen Jiang
    • , Meenakshi Anurag
    • , Jiayi Ji
    • , Seungyeul Yoo
    • , Daniel Cui Zhou
    • , Wen-Wei Liang
    • , Michael Wendl
    • , Pankaj Vats
    • , Steven A. Carr
    • , D.R. Mani
    • , Zhen Zhang
    • , Jiang Qian
    • , Xi S. Chen
    • , Alexander R. Pico
    • , Pei Wang
    • , Arul M. Chinnaiyan
    • , Karen A. Ketchum
    • , Christopher R. Kinsinger
    • , Ana I. Robles
    • , Eunkyung An
    • , Tara Hiltke
    • , Mehdi Mesri
    • , Mathangi Thiagarajan
    • , Alissa M. Weaver
    • , Andrew G. Sikora
    • , Jan Lubiński
    • , Małgorzata Wierzbicka
    • , Maciej Wiznerowicz
    • , Shankha Satpathy
    • , Michael A. Gillette
    • , George Miles
    • , Matthew J. Ellis
    • , Gilbert S. Omenn
    • , Henry Rodriguez
    • , Emily S. Boja
    • , Saravana M. Dhanasekaran
    • , Li Ding
    • , Alexey I. Nesvizhskii
    • , Adel K. El-Naggar
    • , Daniel W. Chan
    • , Hui Zhang
    • , Bing Zhang
    • , Anupriya Agarwal
    • , Matthew L. Anderson
    • , Shayan C. Avanessian
    • , Dmitry Avtonomov
    • , Oliver F. Bathe
    • , Chet Birger
    • , Michael J. Birrer
    • , Lili Blumenberg
    • , William E. Bocik
    • , Uma Borate
    • , Melissa Borucki
    • , Meghan C. Burke
    • , Shuang Cai
    • , Anna Pamela Calinawan
    • , Sandra Cerda
    • , Alyssa Charamut
    • , Lin S. Chen
    • , Shrabanti Chowdhury
    • , Karl R. Clauser
    • , Houston Culpepper
    • , Tomasz Czernicki
    • , Fulvio D'Angelo
    • , Jacob Day
    • , Stephanie De Young
    • , Emek Demir
    • , Fei Ding
    • , Marcin J. Domagalski
    • , Joseph C. Dort
    • , Brian Druker
    • , Elizabeth Duffy
    • , Maureen Dyer
    • , Nathan J. Edwards
    • , Kimberly Elburn
    • , Tatiana S. Ermakova
    • , David Fenyo
    • , Renata Ferrarotto
    • , Alicia Francis
    • , Stacey Gabriel
    • , Luciano Garofano
    • , Yifat Geffen
    • , Gad Getz
    • , Charles A. Goldthwaite
    • , Linda I. Hannick
    • , Pushpa Hariharan
    • , David N. Hayes
    • , David Heiman
    • , Barbara Hindenach
    • , Katherine A. Hoadley
    • , Galen Hostetter
    • , Martin Hyrcza
    • , Scott D. Jewell
    • , Corbin D. Jones
    • , M. Harry Kane
    • , Alicia Karz
    • , Ramani B. Kothadia
    • , Azra Krek
    • , Chandan Kumar-Sinha
    • , Tao Liu
    • , Hongwei Liu
    • , Weiping Ma
    • , Ewa Malc
    • , Anna Malovannaya
    • , Sailaja Mareedu
    • , Sanford P. Markey
    • , Annette Marrero-Oliveras
    • , Nicollette Maunganidze
    • , Jason E. McDermott
    • , Peter B. McGarvey
    • , John McGee
    • , Piotr Mieczkowski
    • , Simona Migliozzi
    • , Rebecca Montgomery
    • , Chelsea J. Newton
    • , Umut Ozbek
    • , Amanda G. Paulovich
    • , Samuel H. Payne
    • , Dimitar Dimitrov Pazardzhikliev
    • , Amy M. Perou
    • , Francesca Petralia
    • , Lyudmila Petrenko
    • , Paul D. Piehowski
    • , Dmitris Placantonakis
    • , Larisa Polonskaya
    • , Elena V. Ponomareva
    • , Olga Potapova
    • , Liqun Qi
    • , Ning Qu
    • , Shakti Ramkissoon
    • , Boris Reva
    • , Shannon Richey
    • , Karna Robinson
    • , Nancy Roche
    • , Karin Rodland
    • , Daniel C. Rohrer
    • , Dmitry Rykunov
    • , Eric E. Schadt
    • , Yan Shi
    • , Yvonne Shutack
    • , Shilpi Singh
    • , Tara Skelly
    • , Richard Smith
    • , Lori J. Sokoll
    • , Jakub Stawicki
    • , Stephen E. Stein
    • , James Suh
    • , Wojciech Szopa
    • , Dave Tabor
    • , Donghui Tan
    • , Darlene Tansil
    • , Guo Ci Teo
    • , Ratna R. Thangudu
    • , Cristina Tognon
    • , Elie Traer
    • , Shirley Tsang
    • , Jeffrey Tyner
    • , Ki Sung Um
    • , Dana R. Valley
    • , Lyubomir Valkov Vasilev
    • , Negin Vatanian
    • , Uma Velvulou
    • , Michael Vernon
    • , Thomas F. Westbrook
    • , Jeffrey R. Whiteaker
    • , Yige Wu
    • , Midie Xu
    • , Lijun Yao
    • , Xinpei Yi
    • , Fengchao Yu
    • , Kakhaber Zaalishvili
    • , Yuriy Zakhartsev
    • , Robert Zelt
    • , Grace Zhao
    •  & Jun Zhu

    Cancer Cell (2021)

  • Onvansertib, a polo-like kinase 1 inhibitor, inhibits prostate stromal cell growth and prostate smooth muscle contraction, which is additive to inhibition by α1-blockers

    • Xiaolong Wang
    • , Bingsheng Li
    • , Anna Ciotkowska
    • , Beata Rutz
    • , Mark G. Erlander
    • , Maya Ridinger
    • , Ruixiao Wang
    • , Alexander Tamalunas
    • , Raphaela Waidelich
    • , Christian G. Stief
    •  & Martin Hennenberg

    European Journal of Pharmacology (2020)

  • Aurora Borealis (Bora), Which Promotes Plk1 Activation by Aurora A, Has an Oncogenic Role in Ovarian Cancer

    • Alfonso Parrilla
    • , Marta Barber
    • , Blanca Majem
    • , Josep Castellví
    • , Juan Morote
    • , José Luis Sánchez
    • , Asunción Pérez-Benavente
    • , Miguel F. Segura
    • , Antonio Gil-Moreno
    •  & Anna Santamaria

    Cancers (2020)

  • Therapeutic opportunities for PLK1 inhibitors: Spotlight on BRCA1-deficiency and triple negative breast cancers

    • Iris Alejandra García
    • , Cintia Garro
    • , Elmer Fernandez
    •  & Gastón Soria

    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (2020)

  • Ste20-like Kinase–mediated Control of Actin Polymerization Is a New Mechanism for Thin Filament–associated Regulation of Airway Smooth Muscle Contraction

    • Yinna Wang
    • , Ruping Wang
    •  & Dale D. Tang

    American Journal of Respiratory Cell and Molecular Biology (2020)

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