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Protein kinase CK2 links extracellular growth factor signaling with the control of p27Kip1 stability in the heart

Nature Medicine volume 14, pages 315–324 (2008)Cite this article

A Corrigendum to this article was published on 01 May 2008

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Abstract

p27Kip1 (p27) blocks cell proliferation through the inhibition of cyclin-dependent kinase-2 (Cdk2). Despite its robust expression in the heart, little is known about both the function and regulation of p27 in this and other nonproliferative tissues, in which the expression of its main target, cyclin E–Cdk2, is known to be very low. Here we show that angiotensin II, a major cardiac growth factor, induces the proteasomal degradation of p27 through protein kinase CK2-α′–dependent phosphorylation. Conversely, unphosphorylated p27 potently inhibits CK2-α′. Thus, the p27–CK2-α′ interaction is regulated by hypertrophic signaling events and represents a regulatory feedback loop in differentiated cardiomyocytes analogous to, but distinct from, the feedback loop arising from the interaction of p27 with Cdk2 that controls cell proliferation. Our data show that extracellular growth factor signaling regulates p27 stability in postmitotic cells, and that inactivation of p27 by CK2-α′ is crucial for agonist- and stress-induced cardiac hypertrophic growth.

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Figure 1: A cytoplasmic complex of CK2-α′ and p27 exists in cardiomyocytes.
Figure 2: CK2-α′ phosphorylates p27 on Ser83 and Thr187.
Figure 3: CK2-α′-mediated p27 degradation is essential for cardiomyocyte hypertrophy.
Figure 4: Mice with targeted homozygous deletion of the p27 gene (p27 KO) develop age-dependent cardiac hypertrophy.
Figure 5: CK2-α′ is important for Ang II action in vivo: protein transduction of KD CK2-α′ or p27ΔPi abrogates cardiac hypertrophy in response to Ang II treatment in WT mice, and transduction of recombinant active CK2-α′ evokes cardiac hypertrophy in the absence of Ang II.
Figure 6: Constitutively inactive KD CK2-α′ does not inhibit cardiac hypertrophy in p27 KO mice.

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  • 21 March 2008

    In the version of this article initally published, one author, Junfeng An, was missing from the author list and the Author Contributions section. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank D.W. Litchfield (The University of Western Ontario) for the gift of antibodies to CK2-α′ and CK2-β subunits. This research was supported by Canadian Institutes of Health Research (MOP-81194) and grants from the Deutsche Forschungsgemeinschaft (Ha-1777/7-3, Ha-1777/9-1) to R.v.H., the Volkswagen-Stiftung (Lichtenberg program) and Bundesministerium für Bildung und Forschung (Center for Stroke Research Berlin) to M.E.

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Authors and Affiliations

  1. Division of Cardiology, University Network Hospitals and Toronto General Research Institute, 200 Elizabeth Street, Toronto, M5G 2C4, Canada

    Ludger Hauck & Rüdiger von Harsdorf

  2. McEwen Centre for Regenerative Medicine, 200 Elizabeth Street, Toronto, M5G 2C4, Canada

    Ludger Hauck & Rüdiger von Harsdorf

  3. Department of Neurology, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, Berlin, 10117, Germany

    Christoph Harms, Karen Gertz & Matthias Endres

  4. Center for Stroke Research Berlin, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, Berlin, 10117, Germany

    Matthias Endres

  5. Department of Cardiology, Campus Virchow Clinic, Charitè, Humboldt University, Augustenburger Platz 1, Berlin, 13353, Germany

    Junfeng An, Jens Rohne & Rainer Dietz

  6. Max-Delbrück Center for Molecular Medicine, Robert-Rossle-Strasse 10, Berlin, 13092, Germany

    Rainer Dietz

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Contributions

J.R. performed the two-hybrid screen and contributed to the in vitro experiments. C.H., K.G. and M.N. performed some of the animal experiments and contributed to the in vivo analysis of the mice. J.A. contributed to the generation of recombinant TAT proteins. L.H., R.D. and R.v.H. carried out experimental design, data analysis and manuscript preparation. R.v.H. supervised L.H. and J.R.

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Correspondence to Rüdiger von Harsdorf.

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Hauck, L., Harms, C., An, J. et al. Protein kinase CK2 links extracellular growth factor signaling with the control of p27Kip1 stability in the heart. Nat Med 14, 315–324 (2008). https://doi.org/10.1038/nm1729

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