Abstract
Epidermal growth factor (EGF) induces cell proliferation in a variety of cell types by binding to a prototype transmembrane tyrosine kinase receptor1,2. Ligation of this receptor by EGF activates Erk1 and Erk2, members of the mitogen-activated protein (MAP) kinase family, through a Ras-dependent signal transduction pathway3,4,5. Despite our detailed understanding of these events, the exact mechanism by which EGF causes cells to proliferate is unclear. Big MAP kinase (Bmk1), also known as Erk5, is a member of the MAP kinase family that is activated in cells in response to oxidative stress, hyperosmolarity and treatment with serum6,7. Here we show that EGF is a potent activator of Bmk1. In contrast to Erk1/2, EGF-mediated activation of Bmk1 occurs independently of Ras and requires the MAP-kinase kinase Mek5. Expression of a dominant-negative form of Bmk1 blocks EGF-induced cell proliferation and prevents cells from entering the S phase of the cell cycle. These results demonstrate that Bmk1 is part of a distinct MAP-kinase signalling pathway that is required for EGF-induced cell proliferation and progression through the cell cycle.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Yarden, Y. & Ullrich, A. Growth factor receptor tyrosine kinases. Annu. Rev. Biochem. 57, 443–478 (1988).
Ullrich, A. & Schlesinger, J. Signal transduction by receptors with tyrosine kinase activity Cell 61, 203–212 (1990).
Su, B. & Karin, M. Mitogen-activated protein kinase cascades and regulation of gene expression Curr. Opin. Immunol. 8, 402–411 (1996).
Johnson, G. L. & Vaillancourt, R. R. Sequential protein kinase reactions controlling cell growth and differentiation Curr. Opin. Cell Biol. 6, 230–238 (1994).
Katz, M. E. & McCormick, F. Signal transduction from multiple Ras effectors Curr. Opin. Genet. Dev. 7, 75–79 (1997).
Abe, J.-I., Kushuhara, M., Ulevitch, R. J., Berk, B. C. & Lee, J.-D. Big mitogen-activated protein kinase 1 (BMK1) is a redox-sensitive kinase J. Biol. Chem. 271, 16586–16590 (1996).
Kato, Y. et al . BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C EMBO J. 16, 7054–7066 (1997).
Li, J. J. & Herskowitz, I. Isolation of ORC6 a component of the yeast origin recognition complex by a one-hybrid system System 262, 1870–1874 (1993).
Lange-Carter, C. A. & Johnson, G. L. Ras-dependent growth factor regulation of MEK kinase in PC12 cells Science 265, 1458–1461 (1994).
Minden, A. et al . Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK Science 266, 1719–1723 (1994).
Zhou, G., Bao, Z. Q. & Dixon, J. E. Components of a new human protein kinase signal transduction pathway J. Biol. Chem. 270, 12665–12669 (1995).
Soule, H. D. et al . Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10 Cancer Res. 50, 6075–6086 (1990).
Pages, G. et al . Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation Proc. Natl Acad. Sci. USA 90, 8319–8323 (1993).
Kovary, K. & Bravo, R. The jun and fos protein families are both required for cell cycle progression in fibroblasts Mol. Cell Biol. 11, 4466–4472 (1991).
Barr, M. M., Tu, H., Van Aeist, L. & Wigler, M. Identification of Ste4 as a potential regulator of Byr2 in the sexual response pathway of Schizosaccharomyces pombe Mol. Cell. Biol. 16, 5597–5603 (1996).
Libermann, T. A. et al . Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313, 144–147 (1985).
Velu, T. J. et al . Epidermal-growth-factor-dependent transformation by a human EGF receptor proto-oncogene Science 238, 1408–1410 (1987).
Merlino, G. T. et al . Amplification and enhanced expression of the epidermal growth factor receptor gene in A431 human carcinoma cells Science 224, 417–419 (1984).
Han, J. et al . Characterization of the structure and function of a novel MAP kinase kinase (MKK6) J. Biol. Chem. 271, 2886–2891 (1996).
White, M. A. et al . Multiple Ras functions can contribute to mammalian cell transformation Cell 80, 533–541 (1995).
Minden, A., Lin, A., Claret, F.-X., Abo, A. & Karin, K. Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs Cell 81, 1147–1157 (1995).
Huang, S. et al . Apoptosis signaling pathway in T cells is composed of ICE/Ced-3 family proteases and MAP kinase kinase 6b Immunity 6, 739–749 (1997).
Chang, M. W., Barr, E., Lu, M. M., Barton, K. & Leiden, J. M. Adenovirus-mediated over-expression of the cyclin/cyclin-dependent kinase inhibitor p21 inhibits vascular smooth muscle cell proliferation and neointima formation in the rat carotid artery model of balloon angioplasty J. Clin. Invest. 96, 2260–2268 (1995).
Bett, A. J., Haddara, W., Prevec, L. & Graham, F. L. An efficient and flexible system for construction of adenovirus vectors with insertions or deletions in early regions 1 and 3 Proc. Natl Acad. Sci. USA 91, 8802–8806 (1994).
Jomary, C. et al . Adenovirus-mediated gene transfer to murine retinal cells in vitro and in vivo FEBS Lett. 347, 117–122 (1994).
Stein, G. S. et al . in A Laboratory Handbook (ed. Celis, J.) 282–287 (Danish Centre for Human Genome Research, Academic, San Diego, (1994)).
Draetta, G. & Beach, D. Activation of cdc2 protein kinase during mitosis in human cells: cell cycle-dependent phosphorylation and subunit rearrangement Cell 54, 17–26 (1988).
Hoy, C. A., Seamer, L. C. & Shimke, R. T. Thermal denaturation of DNA for immunochemical staining of incorporated bromodeoxyuridine (BrdUrd): critical factors that affect the amount of fluorescence and the shape of BrdUrd/DNA histogram Cytometry 10, 718–725 (1989).
Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B. & Craig, R. W. Participation of p53 protein in the cellular response to DNA damage Cancer Res. 51, 6304–6311 (1991).
Acknowledgements
We thank M. Karin for Ras(V12G) and Ras(T17N) expression vectors, and B. Chastain for secretarial assistance. This work was supported by grants from the NIH (to J.-D.L. and R.J.U.) and the American Heart Association (to J.-D.L.) and by postdoctoral fellowships from the American Heart Association, California Affiliate (R.I.T.) and the Research Center for Infectious Disease, Aichi Medical University (Y.K.).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kato, Y., Tapping, R., Huang, S. et al. Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor. Nature 395, 713–716 (1998). https://doi.org/10.1038/27234
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/27234
This article is cited by
-
Etiopathogenic role of ERK5 signaling in sarcoma: prognostic and therapeutic implications
Experimental & Molecular Medicine (2023)
-
DDIAS, DNA damage-induced apoptosis suppressor, is a potential therapeutic target in cancer
Experimental & Molecular Medicine (2023)
-
Studying molecular signaling in major angiogenic diseases
Molecular and Cellular Biochemistry (2022)
-
Irradiation with a red light-emitting diode enhances the proliferation of stem cells of apical papilla via the ERK5 signalling pathway
Lasers in Medical Science (2022)
-
The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival
Cellular and Molecular Life Sciences (2022)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.