The cytoplasmic phosphatase DUSP6 and its nuclear counterpart DUSP5 are negative regulators of RAS/ERK signalling. Here we use deletion of either Dusp5 or Dusp6 to explore the roles of these phosphatases in a murine model of KRAS G12D -driven pancreatic cancer. By 56-days, loss of either DUSP5 or DUSP6 causes a significant increase in KRAS G12D -driven pancreatic hyperplasia. This is accompanied by increased pancreatic acinar to ductal metaplasia (ADM) and the development of pre-neoplastic pancreatic intraepithelial neoplasia (PanINs). In contrast, by 100-days, pancreatic hyperplasia is reversed with significant atrophy of pancreatic tissue and weight loss observed in animals lacking either DUSP5 or DUSP6. On further ageing, Dusp 6 −/− mice display accelerated development of metastatic pancreatic ductal adenocarcinoma (PDAC), while in Dusp5 −/− animals, although PDAC development is increased this process is attenuated by atrophy of pancreatic acinar tissue and severe weight loss in some animals before cancer could progress. Our data suggest that despite a common target in the ERK MAP kinase, DUSP5 and DUSP6 play partially non-redundant roles in suppressing oncogenic KRAS G12D signalling, thus retarding both tumour initiation and progression. Our data suggest that loss of either DUSP5 or DUSP6, as observed in certain human tumours, including the pancreas, could promote carcinogenesis.

CELL BIOLOGY Correction for “Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling,” by AndrewM. Kidger, Linda K. Rushworth, Julia Stellzig, Jane Davidson, Christopher J. Bryant, Cassidy Bayley, Edward Caddye, Tim Rogers, Stephen M. Keyse, and Christopher J. Caunt, which was first published January 4, 2017; 10.1073/pnas.1614684114 (Proc Natl Acad Sci USA 114:E317–E326). The authors wish to note the following: “Since the publication of our paper, we have become aware that the quantitative data presented in Fig. 1B do not represent the full raw data set provided in the supporting information deposited online at https://doi.org/ 10.15125/BATH-00317. We are therefore publishing a corrected version of Fig. 1 in which the graphs in panel B have been replaced by those generated from the complete online dataset. The result and the conclusions drawn are unchanged. A minor correction has also been made to the figure legend to reflect the altered P values that result from use of the complete dataset.” The corrected Fig. 1 and its corrected legend appear below.

Deregulated extracellular signal-regulated kinase (ERK) signaling drives cancer growth. Normally, ERK activity is self-limiting by the rapid inactivation of upstream kinases and delayed induction of dual-specificity MAP kinase phosphatases (MKPs/DUSPs). However, interactions between these feedback mechanisms are unclear. Here we show that, although the MKP DUSP5 both inactivates and anchors ERK in the nucleus, it paradoxically increases and prolongs cytoplasmic ERK activity. The latter effect is caused, at least in part, by the relief of ERK-mediated RAF inhibition. The importance of this spatiotemporal interaction between these distinct feedback mechanisms is illustrated by the fact that expression of oncogenic BRAFV600E, a feedback-insensitive mutant RAF kinase, reprograms DUSP5 into a cell-wide ERK inhibitor that facilitates cell proliferation and transformation. In contrast, DUSP5 deletion causes BRAF(V600E)-induced ERK hyperactivation and cellular senescence. Thus, feedback interactions within the ERK pathway can regulate cell proliferation and transformation, and suggest oncogene-specific roles for DUSP5 in controlling ERK signaling and cell fate.