The role of dual-specificity phosphatase 6 (DUSP6) in modulating the oncogenic potential of Ras/ERK signalling

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Dual-specificity MAP kinase (MAPK) phosphatases (DUSPs or MKPs) are key negative regulators of MAPK pathway activity and thus the biological outcome of signalling. The Ras-Raf-ERK pathway is abnormally activated in a wide variety of human cancers, including lung, pancreas and malignant melanoma. Furthermore, the expression of MKPs is often either reduced or increased as cancers develop indicating that MKPs, by modulating pathway activity, may influence tumour initiation and/or development. The growth factor inducible phosphatase DUSP6/MKP-3 is a specific negative feedback regulator of the classical ERK1 and ERK2 MAPKs in the cytoplasm. We have generated mice carrying a conditional (floxed) DUSP6 allele and are studying the effects of gene loss in both cultured cells and in mouse models of cancer. Thus far, we have demonstrated that deletion of DUSP6/MKP-3 sensitises mice to DMBA/TPA-inducible skin carcinogenesis, demonstrating a tumour suppressor role for this phosphatase. Current and future studies are aimed at determining if DUSP6/MKP-3 plays a wider role in mutant Ras-induced tumours in more clinically relevant tissues such as pancreas and lung and to use both tissues and cell lines cultured from these animals to determine the relevant MAPK targets affected by DUSP6 deletion and how these might act to promote cancer development.