Abstract
The mitogen-activated protein kinase (MAPK) pathway is a highlyconserved eukaryotic signalling cascade that converts extracellular signals into various outputs, such as cell growth and differentiation1,2,3. MAPK is phosphorylated and activated by a specific MAPK kinase (MAPKK)4: MAPKK is therefore considered to be an activating regulator of MAPK. Pmk1 is a MAPK that regulates cell integrity5 and which, with calcineurin phosphatase, antagonizes chloride homeostasis6 in fission yeast. We have now identified Pek1, a MAPKK for Pmk1 MAPK. We show here that Pek1, in its unphosphorylated form, acts as a potent negative regulator of Pmk1 MAPK signalling. Mkh17, an upstream MAPKK kinase (MAPKKK), converts Pek1 from being an inhibitor to an activator. Our results indicate that Pek1 has a dual stimulatory and inhibitory function which depends on its phosphorylation state. This switch-like mechanism could contribute to the all-or-none physiological response mediated by the MAPK signalling pathway.
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
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Herskowitz, I. MAP kinase pathways in yeast: for mating and more. Cell 80, 187–197 (1995).
Nishida, E. & Gotoh, Y. The MAP kinase cascade is essential for diverse signal transduction pathways. Trends Biochem. Sci. 18, 128–131 (1993).
Levin, D. E. & Errede, B. The proliferation of MAP kinase signaling pathways in yeast. Curr. Biol. 7, 197–202 (1995).
Marshall, C. J. MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. Curr. Opin. Genet. Dev. 4, 82–89 (1994).
Toda, T.et al. The fission yeast pmk1+ gene encodes a novel mitogen-activated protein kinase homolog which regulates cell integrity and functions coordinately with the protein kinase C pathway. Mol. Cell. Biol. 16, 6752–6764 (1996).
Sugiura, R.et al. pmp1+, a suppressor of calcineurin deficiency, encodes a novel MAP kinase phosphatase in fission yeast. EMBO J. 17, 140–148 (1998).
Sengar, A. S., Markley, N. A., Marini, N. J. & Young, D. Mkh1, a MEK kinase required for cell wall integrity and proper response to osmotic and temperature stress in Schizosaccharomyces pombe. Mol. Cell. Biol. 17, 3508–3519 (1997).
Yoshida, T., Toda, T. & Yanagida, M. Acalcineurin-like gene ppb1+ in fission yeast: mutant defects in cytokinesis, cell polarity, mating and spindle pole body positioning. J. Cell Sci. 107, 1725–1735 (1994).
Crews, C. M., Alessandrini, A. & Erikson, R. L. The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science 258, 478–480 (1992).
Irie, K.et al. MKK1 and MKK2, which encode Saccharomyces cerevisiae mitogen-activated protein kinase-kinase homologs, function in the pathway mediated by protein kinase C. Mol. Cell. Biol. 13, 3076–3083 (1993).
Toda, T., Shimanuki, M. & Yanagida, M. Fission yeast genes that confer resistance to staurosporine encode an AP-1-like transcription factor and a protein kinase related to the mammalian ERK1/MAP2 and budding yeast FUS3 and KSS1 kinases. Genes Dev. 5, 60–73 (1991).
Millar, J. B., Buck, V. & Wilkinson, M. G. Pyp1 and Pyp2 PTPases dephosphorylate an osmosensing MAP kinase controlling cell size at division in fission yeast. Genes Dev. 9, 2117–2130 (1995).
Shiozaki, K. & Russell, P. Cell-cycle control linked to extracellular environment by MAP kinase pathway in fission yeast. Nature 378, 739–743 (1995).
Kato, T.et al. Stress signal, mediated by a Hog1-like MAP kinase, controls sexual development in fission yeast. FEBS Lett. 378, 207–212 (1996).
Zaitsevskaya, C. T. & Cooper, J. A. Spm1, a stress-activated MAP kinase that regulates morphogenesis in S. pompe. EMBO J. 16, 1318–1331 (1997).
McLeod, M., Stein, M. & Beach, D. The product of the mei3+ gene, expressed under control of the mating-type locus, induces meiosis and sporulation in fission yeast. EMBO J. 6, 729–736 (1987).
Cook, J. G., Bardwell, L. & Thorner, J. Inhibitory and activating functions for MAPK Kss1 in the S. cerevisiae filamentous-growth signalling pathway. Nature 390, 85–88 (1997).
Madhani, H. D., Styles, C. A. & Fink, G. R. MAP kinases with distinct inhibitory functions impart signaling specificity during yeast differentiation. Cell 91, 673–684 (1997).
Murray, A. W. MAP kinases in meiosis. Cell 92, 157–159 (1998).
Ferrell, J. E. & Machleder, E. M. The biochemical basis of an all-or-none cell fate switch in Xenopus oocytes. Science 280, 895–898 (1998).
Rothstein, R. J. One-step gene disruption in yeast. Methods Enzymol. 101, 202–211 (1983).
Keeney, J. B. & Boeke, J. D. Efficient targeted integration at leu1-32 and ura4-294 in Schizosaccharomyces pombe. Genetics 136, 849–856 (1994).
Neiman, A. M. & Herskowitz, I. Reconstitution of a yeast protein kinase cascade in vitro: Activation of the yeast MEK homologue STE7 by STE11. Proc. Natl Acad. Sci. USA 91, 3398–3402 (1994).
Zarzov, P., Mazzoni, C. & Mann, C. The SLT2(MPK1) MAP kinase is activated during periods of polarized cell growth in yeast. EMBO J. 15, 83–91 (1996).
Beach, D., Piper, M. & Nurse, P. Construction of a Schizosaccharomyces pombe gene bank in a yeast bacterial shuttle vector and its use to isolate genes by complementation. Mol. Gen. Genet. 187, 326–329 (1982).
Levin, D. E. & Bishop, M. Aputative protein kinase gene (kin1+) is important for growth polarity in Schizosaccharomyces pombe. Proc. Natl Acad. Sci. USA 87, 8272–8276 (1990).
Barbet, N., Muriel, W. J. & Carr, A. M. Versatile shuttle vectors and genomic libraries for use with Schizosaccharomyces pombe. Gene 114, 59–66 (1992).
Moreno, S., Klar, A. & Nurse, P. Molecular genetic analysis of fission yeast Schizosaccharomyces pombe. Methods Enzymol. 194, 795–823 (1991).
Acknowledgements
We thank S. O. Sio, Y. Minami and K. Tanaka for comments on the manuscript, M.Yanagida and H. Mukai for helpful suggestions, and Y. Kawabe for technical assistance. This work was supported in part by research grants from the Ministry of Education, Science and Culture of Japan.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sugiura, R., Toda, T., Dhut, S. et al. The MAPK kinase Pek1 acts as a phosphorylation-dependent molecular switch. Nature 399, 479–483 (1999). https://doi.org/10.1038/20951
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/20951
This article is cited by
-
MAPK-dependent control of mitotic progression in S. pombe
BMC Biology (2024)
-
Rae1-mediated nuclear export of Rnc1 is an important determinant in controlling MAPK signaling
Current Genetics (2018)
-
Nitric oxide as a signaling molecule in the fission yeast Schizosaccharomyces pombe
Protoplasma (2009)
-
Feedback regulation of MAPK signalling by an RNA-binding protein
Nature (2003)
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.