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

摘要: 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 dual-specificity MAP phosphatases (MKPs/DUSPs). However, interactions between these feedback mechanisms are unclear. Here we show that, although MKP DUSP5 both inactivates anchors in nucleus, it paradoxically increases prolongs cytoplasmic activity. The latter effect caused, at least part, relief ERK-mediated RAF inhibition. importance this spatiotemporal interaction distinct illustrated fact that expression oncogenic BRAFV600E, a feedback-insensitive mutant kinase, reprograms into cell-wide inhibitor facilitates cell proliferation transformation. In contrast, deletion causes BRAFV600E-induced hyperactivation cellular senescence. Thus, within pathway can regulate transformation, suggest oncogene-specific roles for controlling fate.