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

ABSTRACT: 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 BRAF^V600E, a feedback-insensitive mutant RAF kinase, reprograms DUS

SUBMITTER: Kidger AM 

PROVIDER: S-EPMC5255582 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature