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A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth


Cell growth, an increase in mass and size, is a highly regulated cellular event. The Akt/mTOR (mammalian target of rapamycin) signalling pathway has a central role in the control of protein synthesis and thus the growth of cells, tissues and organisms1. A striking example of a physiological context requiring rapid cell growth is tissue repair in response to injury2. Here we show that keratin 17, an intermediate filament protein rapidly induced in wounded stratified epithelia3, regulates cell growth through binding to the adaptor protein 14-3-3σ. Mouse skin keratinocytes lacking keratin 17 (ref. 4) show depressed protein translation and are of smaller size, correlating with decreased Akt/mTOR signalling activity. Other signalling kinases have normal activity, pointing to the specificity of this defect. Two amino acid residues located in the amino-terminal head domain of keratin 17 are required for the serum-dependent relocalization of 14-3-3σ from the nucleus to the cytoplasm, and for the concomitant stimulation of mTOR activity and cell growth. These findings reveal a new and unexpected role for the intermediate filament cytoskeleton in influencing cell growth and size by regulating protein synthesis.

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Figure 1: K17 -/- keratinocytes are smaller than wild-type cells in the embryonic ectoderm and in primary cultures.
Figure 2: Depressed protein translation and Akt/mTOR activity in K17 -/- keratinocytes.
Figure 3: Changes in subcellular localization of 14-3-3 proteins in K17 -/- keratinocytes.
Figure 4: Role of K17 in retaining 14-3-3 in the cytoplasm and promoting protein translation and cell growth.


  1. Kozma, S. C. & Thomas, G. Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K. Bioessays 24, 65–71 (2002)

    CAS  Article  Google Scholar 

  2. Martin, P. Wound healing—aiming for perfect skin regeneration. Science 276, 75–81 (1997)

    CAS  Article  Google Scholar 

  3. Paladini, R. D., Takahashi, K., Bravo, N. S. & Coulombe, P. A. Onset of re-epithelialization after skin injury correlates with a reorganization of keratin filaments in wound edge keratinocytes: defining a potential role for keratin 16. J. Cell Biol. 132, 381–397 (1996)

    CAS  Article  Google Scholar 

  4. McGowan, K. M. et al. Keratin 17 null mice exhibit age- and strain-dependent alopecia. Genes Dev. 16, 1412–1422 (2002)

    CAS  Article  Google Scholar 

  5. Omary, M. B., Coulombe, P. A. & McLean, W. H. Intermediate filament proteins and their associated diseases. N. Engl. J. Med. 351, 2087–2100 (2004)

    CAS  Article  Google Scholar 

  6. Bereiter-Hahn, J. in Biology of the Integument-Vertebrates (eds Bereiter-Hahn, J., Matoltsy, A. G. & Richards, K. S.) 443–463 (Springer-Verlag, New York, 1986)

    Book  Google Scholar 

  7. DePianto, D. & Coulombe, P. A. Intermediate filaments and tissue repair. Exp. Cell Res. 301, 68–76 (2004)

    CAS  Article  Google Scholar 

  8. Coulombe, P. A. & Wong, P. Cytoplasmic intermediate filaments revealed as dynamic and multipurpose scaffolds. Nature Cell Biol. 6, 699–706 (2004)

    CAS  Article  Google Scholar 

  9. Mazzalupo, S., Wong, P., Martin, P. & Coulombe, P. A. Role for keratins 6 and 17 during wound closure in embryonic mouse skin. Dev. Dyn. 226, 356–365 (2003)

    CAS  Article  Google Scholar 

  10. Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes Dev. 18, 1926–1945 (2004)

    CAS  Article  Google Scholar 

  11. Fingar, D. C., Salama, S., Tsou, C., Harlow, E. & Blenis, J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 16, 1472–1487 (2002)

    CAS  Article  Google Scholar 

  12. Hardie, D. G. The AMP-activated protein kinase pathway—new players upstream and downstream. J. Cell Sci. 117, 5479–5487 (2004)

    CAS  Article  Google Scholar 

  13. Meijer, A. J. & Codogno, P. Regulation and role of autophagy in mammalian cells. Int. J. Biochem. Cell Biol. 36, 2445–2462 (2004)

    CAS  Article  Google Scholar 

  14. Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membrane after processing. EMBO J. 19, 5720–5728 (2000)

    CAS  Article  Google Scholar 

  15. Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005)

    ADS  CAS  Article  Google Scholar 

  16. Prasad, G. L., Valverius, E. M., McDuffie, E. & Cooper, H. L. Complementary DNA cloning of a novel epithelial cell marker protein, HME1, that may be down-regulated in neoplastic mammary cells. Cell Growth Differ. 3, 507–513 (1992)

    CAS  PubMed  Google Scholar 

  17. Fu, H., Subramanian, R. R. & Masters, S. C. 14-3-3 proteins: structure, function, and regulation. Annu. Rev. Pharmacol. Toxicol. 40, 617–647 (2000)

    CAS  Article  Google Scholar 

  18. Brunet, A. et al. 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. J. Cell Biol. 156, 817–828 (2002)

    CAS  Article  Google Scholar 

  19. Liao, J. & Omary, M. B. 14-3-3 proteins associate with phosphorylated simple epithelial keratins during cell cycle progression and act as a solubility cofactor. J. Cell Biol. 133, 345–357 (1996)

    CAS  Article  Google Scholar 

  20. Tzivion, G., Luo, Z. J. & Avruch, J. Calyculin A-induced vimentin phosphorylation sequesters 14-3-3 and displaces other 14-3-3 partners in vivo. J. Biol. Chem. 275, 29772–29778 (2000)

    CAS  Article  Google Scholar 

  21. Ku, N. O., Michie, S., Resurreccion, E. Z., Broome, R. L. & Omary, M. B. Keratin binding to 14-3-3 proteins modulates keratin filaments and hepatocyte mitotic progression. Proc. Natl Acad. Sci. USA 99, 4373–4378 (2002)

    ADS  CAS  Article  Google Scholar 

  22. Beck, T. & Hall, M. N. The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors. Nature 402, 689–692 (1999)

    ADS  CAS  Article  Google Scholar 

  23. Bertram, P. G., Zeng, C., Thorson, J., Shaw, A. S. & Zheng, X. F. The 14-3-3 proteins positively regulate rapamycin-sensitive signaling. Curr. Biol. 8, 1259–1267 (1998)

    CAS  Article  Google Scholar 

  24. Li, Y., Inoki, K., Yeung, R. & Guan, K. L. Regulation of TSC2 by 14-3-3 binding. J. Biol. Chem. 277, 44593–44596 (2002)

    CAS  Article  Google Scholar 

  25. Yaffe, M. B. et al. The structural basis for 14-3-3:phosphopeptide binding specificity. Cell 91, 961–971 (1997)

    CAS  Article  Google Scholar 

  26. Coulombe, P. A., Tong, X., Mazzalupo, S., Wang, Z. & Wong, P. Great promises yet to be fulfilled: defining keratin intermediate filament function in vivo. Eur. J. Cell Biol. 83, 735–746 (2004)

    CAS  Article  Google Scholar 

  27. Bernot, K. M., Coulombe, P. A. & Wong, P. Skin: an ideal model system to study keratin genes and proteins. Methods Cell Biol. 78, 453–487 (2004)

    CAS  Article  Google Scholar 

  28. Redpath, N. T., Foulstone, E. J. & Proud, C. G. Regulation of translation elongation factor-2 by insulin via a rapamycin-sensitive signalling pathway. EMBO J. 15, 2291–2297 (1996)

    CAS  Article  Google Scholar 

  29. Kim, D. H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002)

    CAS  Article  Google Scholar 

  30. Staddon, J. M., Smales, C., Schulze, C., Esch, F. S. & Rubin, L. L. p120, a p120-related protein (p100), and the cadherin/catenin complex. J. Cell Biol. 130, 369–381 (1995)

    CAS  Article  Google Scholar 

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We thank members of the Coulombe laboratory for support, B. Vogelstein for providing 14-3-3σ antibody and cDNA, T. Yoshimori for providing anti-LC3 antibody, and C. Parent, S. Craig, J. Lorsch, D. Ginty, S. H. Cha, S. Kim, C. S. Lee and C. Moon for advice. This work was supported by a grant from the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) to P.A.C.

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Correspondence to Pierre A. Coulombe.

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Supplementary information

Supplementary Figure Legends

This file contains text to accompany the below Supplementary Figures. (DOC 32 kb)

Supplementary Figure 1

Complement to analyses of K17 null keratinocytes. (JPG 427 kb)

Supplementary Figure 2

Additional analyses of Akt/mTOR pathway in K17 null keratinocytes (JPG 517 kb)

Supplementary Figure 3

Identification of 14-3-3σ as a keratin 17-binding protein. (JPG 1491 kb)

Supplementary Figure 4

Further analysis of the significance of the K17/14-3-3σ interaction for regulation of protein synthesis and growth in skin keratinocytes. (JPG 386 kb)

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Kim, S., Wong, P. & Coulombe, P. A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth. Nature 441, 362–365 (2006).

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