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Dual-specificity MAP kinase phosphatases (MKPs) and cancer

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Abstract

There are ten mitogen-activated protein kinase (MAPK) phosphatases (MKPs) that act as negative regulators of MAPK activity in mammalian cells and these can be subdivided into three groups. The first comprises DUSP1/MKP-1, DUSP2/PAC1, DUSP4/MKP-2 and DUSP5/hVH-3, which are inducible nuclear phosphatases. With the exception of DUSP5, these MKPs display a rather broad specificity for inactivation of the ERK, p38 and JNK MAP kinases. The second group contains three closely related ERK-specific and cytoplasmic MKPs encoded by DUSP6/MKP-3, DUSP7/MKP-X and DUSP9/MKP-4. The final group consists of three MKPs DUSP8/hVH-5, DUSP10/MKP-5 and DUSP16/MKP-7 all of which preferentially inactivate the stress-activated p38 and JNK MAP kinases. Abnormal MAPK signalling will have important consequences for processes critical to the development and progression of human cancer. In addition, MAPK signalling also plays a key role in determining the response of tumour cells to conventional cancer therapies. The emerging roles of the dual-specificity MKPs in the regulation of MAPK activities in normal tissues has highlighted the possible pathophysiological consequences of either loss (or gain) of function of these enzymes as part of the oncogenic process. This review summarises the current evidence implicating the dual-specificity MKPs in the initiation and development of cancer and also on the outcome of treatment.

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Abbreviations

ALL:

acute lymphocytic leukaemia

AML:

acute myeloid leukaemia

BM:

bone marrow

DUSP:

dual-specificity protein phosphatase

ERK:

extracellular-signal regulated kinase

JNK:

c-Jun amino-terminal kinase

MAPK:

mitogen-activated protein kinase

MEF:

mouse embryo fibroblast

MKK or MEK:

MAPK kinase

MKKK or MEKK:

MAPK kinase kinase

MKP:

MAP kinase phosphatase

NSCLC:

non-small cell lung cancer

SCA:

serous ovarian carcinoma

SAGE:

serial analysis of gene expression

SBT:

serous borderline ovarian tumour

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Acknowledgements

Work in my laboratory is supported by Cancer Research UK.

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Keyse, S.M. Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev 27, 253–261 (2008). https://doi.org/10.1007/s10555-008-9123-1

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