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Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor

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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.

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Figure 1: EGF is a potent inducer of Bmk1 activation.
Figure 2: EGF activates Bmk1 through a Ras-independent and Mek5-dependent pathway.
Figure 3: Bmk1 is required for EGF-dependent cell proliferation.
Figure 4: Bmk1 is required for entry of cells into S phase.

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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.).

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  1. Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Yutaka Kato, Richard I. Tapping, Shuang Huang, Mark H. Watson, Richard J. Ulevitch & Jiing-Dwan Lee

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  1. Yutaka Kato
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  2. Richard I. Tapping
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  3. Shuang Huang
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  4. Mark H. Watson
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  5. Richard J. Ulevitch
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  6. Jiing-Dwan Lee
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Correspondence to Jiing-Dwan Lee.

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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

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