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

作者：Kidger Andrew M; Rushworth Linda K; Stellzig Julia; Davidson Jane; Bryant Christopher J; Bayley Cassidy; Caddye Edward; Rogers Tim; Keyse Stephen M; Caunt Christopher J

来源：Proceedings of the National Academy of Sciences of the United States of America, 2017, 114(3): E317-E326.

DOI：10.1073/pnas.1614684114

• ERK
• MAPK
• MKP
• DUSP
• signaling

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.

• 出版日期2017-1-17