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Cot protooncoprotein activates the dual specificity kinases MEK-1 and SEK-1 and induces differentiation of PC12 cells

Oncogene volume 18, pages 1391–1400 (1999)Cite this article

Abstract

Mitogenic signals initiated at the plasma membrane are transmitted to the nucleus through an intricate signalling network. We identified the protooncoprotein Cot as a new component of mitogenic signalling cascades, which activates both the classic cytoplasmic cascade and the SAPK stress pathway. Wildtype and activated Cot phosphorylate and activate MEK-1 and SEK-1 in vitro. These findings are consistent with the sequence homology between Cot and the rat gene Tpl-2. Expression of oncogenic Cot in 293, NIH3T3 and PC12 cells leads to in vivo phosphorylation of endogenous c-Jun and Erk-1/2 suggesting that the serine/threonine kinase Cot functions beside c-Raf-1 and Mos as a direct activator of MEK-1. Furthermore, we have examined the biological effects of Cot on the phenotype of fibroblastic and neuronal cells. In order to test a potential c-Raf-1 dependency of Cot transformation, the effect of oncogenic Cot on Raf revertant CHP25 cells was determined. Cot could restore the transformed phenotype indicating that Cot transformation is not dependent on active c-Raf-1 and that Cot is not a target for the putative Raf inhibitor, which is presumably active in the revertant cell line. Expression of oncogenic versions of Raf as well as v-Mos leads to differentiation of PC12 cells. Cot also induces neurite outgrowth of PC12 cells. These data are consistent with the role of Cot in the classic mitogenic cascade and suggest that the simultaneously activated JNK/SAPK stress pathway has no antagonistic effects in this context.

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Abbreviations

Cot:

cancer osaka thyroid

ERK:

extracellular signal regulated kinase

MEK:

MAPK/ERK kinase

MAPK:

mitogen activated protein kinase

MKK:

MAPK kinase

SAPK:

stress activated protein kinase

JNK:

c-Jun N-terminal kinase

PSK:

protein serine kinase

PTK:

protein tyrosine kinase

Tpl-2:

tumor progression locus 2

SHOK:

syrian hamster Osaka kanazawa

HA:

hemaglutinin

MOI:

multiplicity of infection

NGF:

nerve growth factor

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Acknowledgements

We are grateful to Jun Myoshi for kindly providing different cot expression plasmids and Cot antibody. We further thank Silvia Pfränger for excellent photographic reproduction, Viktor Wixler, Barbara Bauer and Manuela Schuler for technical assistance, and Carsten Hagemann and Bruce Jordan for critical reading of the manuscript.

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  1. Institut für la Medizinische Strahlenkunde und Zellforschung (MSZ), University of Würzburg,, Versbacher Str. 5, Würzburg, 97078, Germany

    Dorthe Hagemann, Jakob Troppmair & Ulf R Rapp

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  3. Ulf R Rapp
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Hagemann, D., Troppmair, J. & Rapp, U. Cot protooncoprotein activates the dual specificity kinases MEK-1 and SEK-1 and induces differentiation of PC12 cells. Oncogene 18, 1391–1400 (1999). https://doi.org/10.1038/sj.onc.1202431

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