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Role of mitogen-activated protein kinase kinase 4 in cancer

Oncogene volume 26, pages 3172–3184 (2007)Cite this article

Abstract

Mitogen-activated protein (MAP) kinase kinase 4 (MKK4) is a component of stress activated MAP kinase signaling modules. It directly phosphorylates and activates the c-Jun N-terminal kinase (JNK) and p38 families of MAP kinases in response to environmental stress, pro-inflammatory cytokines and developmental cues. MKK4 is ubiquitously expressed and the targeted deletion of the Mkk4 gene in mice results in early embryonic lethality. Further studies in mice have indicated a role for MKK4 in liver formation, the immune system and cardiac hypertrophy. In humans, it is reported that loss of function mutations in the MKK4 gene are found in approximately 5% of tumors from a variety of tissues, suggesting it may have a tumor suppression function. Furthermore, MKK4 has been identified as a suppressor of metastasis of prostate and ovarian cancers. However, the role of MKK4 in cancer development appears complex as other studies support a pro-oncogenic role for MKK4 and JNK. Here we review the biochemical and functional properties of MKK4 and discuss the likely mechanisms by which it may regulate the steps leading to the formation of cancers.

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Acknowledgements

We thank A Sharrocks and S-H Yang for comments on the manuscript. AJW is a Lister Institute-Jenner Research Fellow. RJD is an Investigator of the Howard Hughes Medical Institute.

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  1. Faculty of Life Sciences, University of Manchester, Manchester, UK

    A J Whitmarsh

  2. Howard Hughes Medical Institute, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    R J Davis

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Whitmarsh, A., Davis, R. Role of mitogen-activated protein kinase kinase 4 in cancer. Oncogene 26, 3172–3184 (2007). https://doi.org/10.1038/sj.onc.1210410

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