The regulation of oncogenic signalling through the Ras/MAP kinase pathway by dual-specificity protein phosphatases

Signalling through the classical Ras/ERK MAP kinase pathway is implicated in the genesis and progression of many human tumours carrying activating mutations is upstream pathway effectors such as receptor tyrosine kinases and the Ras family of cellular proto-oncogenes. We are interested in the potential role of a family of dual-specificity MAP kinase phosphatases (DUSPs or MKPs) in modulating the oncogenic potential of these proteins (see Dual-specificity MAP kinase phosphatases (MKPs) and cancer. (Keyse SM. Cancer Metastasis Rev. 2008 27:253-61). MKPs are protein phosphatases that are transcriptionally regulated in response to many of the stimuli that activate MAPK signalling and may operate as negative feedback regulators of pathway activity (see Dual-specificity MAP kinase phosphatases (MKPs): Shaping the outcome of MAP kinase signalling. Caunt CJ, Keyse SM. FEBS J. 2013 280: 489-504). We have generated genetic models lacking MKPs, which specifically regulate ERK1 and ERK2 activity and these will be used to study the role of these enzymes in the spatio-temporal regulation of ERK activation in mammalian cells. Our conditional knockouts will also be used in conjunction with Ras-induced murine models of lung, pancreas and intestinal cancer to dissect the effects of MKP gene loss on tumour incidence and development.