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Semin Cell Dev Biol. 2016 Feb;50:125-32. doi: 10.1016/j.semcdb.2016.01.009. Epub 2016 Jan 11.

The regulation of oncogenic Ras/ERK signalling by dual-specificity mitogen activated protein kinase phosphatases (MKPs).

Author information

1
CR-UK Stress Response Laboratory, Division of Cancer Research, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.
2
CR-UK Stress Response Laboratory, Division of Cancer Research, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK. Electronic address: s.m.keyse@dundee.ac.uk.

Abstract

Dual-specificity MAP kinase (MAPK) phosphatases (MKPs or DUSPs) are well-established negative regulators of MAPK signalling in mammalian cells and tissues. By virtue of their differential subcellular localisation and ability to specifically recognise, dephosphorylate and inactivate different MAPK isoforms, they are key spatiotemporal regulators of pathway activity. Furthermore, as they are transcriptionally regulated as downstream targets of MAPK signalling they can either act as classical negative feedback regulators or mediate cross talk between distinct MAPK pathways. Because MAPKs and particularly Ras/ERK signalling are implicated in cancer initiation and development, the observation that MKPs are abnormally regulated in human tumours has been interpreted as evidence that these enzymes can either suppress or promote carcinogenesis. However, definitive evidence of such roles has been lacking. Here we review recent work based on the use of mouse models, biochemical studies and clinical data that demonstrate key roles for MKPs in modulating the oncogenic potential of Ras/ERK signalling and also indicate that these enzymes may play a role in the response of tumours to certain anticancer drugs. Overall, this work reinforces the importance of negative regulatory mechanisms in modulating the activity of oncogenic MAPK signalling and indicates that MKPs may provide novel targets for therapeutic intervention in cancer.

KEYWORDS:

DUSP5; DUSP6/MKP-3; Dual-specificity phosphatase; Extracellular signal-regulated kinase; MAP kinase; MAP kinase phosphatase; Ras oncogene

PMID:
26791049
PMCID:
PMC5056954
DOI:
10.1016/j.semcdb.2016.01.009
[Indexed for MEDLINE]
Free PMC Article

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