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

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.

Hyperactivation of extracellular signal-regulated kinase (ERK) by RAS-mediated signaling or inhibition of dual specificity phosphatase 6 (DUSP6) is associated with toxicity in lung adenocarcinoma cells with mutations in KRAS or EGFR

“…DUSP6 was the only negative feedback regulatory gene with significantly different levels of expression when we compared tumors with mutations in either KRAS or EGFR with tumors without such mutations (Bonferoni corrected p<0.01, twotailed t-test with Welch's correction). This result is consistent with a role for DUSP6 in regulating EGFR-KRAS-ERK signaling 12,[15][16][17][18][19] . DUSP6 RNA was also present at higher levels in LUADs with EGFR or KRAS mutations than in tumors without such mutations in an independent collection of 83 tumors collected at the BC Cancer Agency (p=0.004), confirming the findings derived from the TCGA dataset ( Fig 2B).…”

Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling

“…ERK-inhibitory proteins, such as the MKP/DUSPs, are therefore often assumed to be tumor suppressors, but both decreased and increased MKP/DUSP expression is linked to tumor progression in different contexts (13). These observations may, at least in part, be explained by evidence showing that high-intensity ERK activation in some cell and tumor types engages tumor suppressive mechanisms, such as senescence (14)(15)(16)(17)(18).…”

Autocrine BMP-4 Signaling Is a Therapeutic Target in Colorectal Cancer

“…Using RNA-seq, we identified DUSP5 as a BMP target gene and determined that DUSP5 was important for the Erk-mediated prosurvival effect of BMP-4 on colorectal cancer cells. DUSP5 is a member of the four inducible nuclear MAPK phosphatases and dephosphorylates Erk1/2 (31,32). DUSP5 has been implicated as a tumor suppressor in various types of cancer, including skin, gastric, prostate, colon, and lung cancer (33)(34)(35)(36).…”