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


Reference:

Kidger, A. M., Rushworth, L. K., Stellzig, J., Davidson, J., Bryant, C. J., Bayley, C., Caddye, E., Rogers, T., Keyse, S. M. and Caunt, C. J., 2017. Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling. Proceedings of the National Academy of Sciences of the United States of America, 114 (3), E317-E326.

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http://dx.doi.org/10.1073/pnas.1614684114

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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 dualspecificity MAP kinase phosphatases (MKPs/DUSPs). However, interactions between these feedback mechanisms are unclear. Here we show that, although theMKP 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 ERKmediated 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 BRAFV600E-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.

Details

Item Type Articles
CreatorsKidger, A. M., Rushworth, L. K., Stellzig, J., Davidson, J., Bryant, C. J., Bayley, C., Caddye, E., Rogers, T., Keyse, S. M. and Caunt, C. J.
DOI10.1073/pnas.1614684114
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URLURL Type
http://www.scopus.com/inward/record.url?scp=85009727885&partnerID=8YFLogxKUNSPECIFIED
http://dx.doi.org/10.1073/pnas.1614684114Free Full-text
Uncontrolled Keywordsdusp,erk,mapk,mkp,signaling
DepartmentsFaculty of Science > Biology & Biochemistry
Faculty of Science > Mathematical Sciences
Research CentresEPSRC Centre for Doctoral Training in Statistical Mathematics (SAMBa)

Centre for Mathematical Biology
RefereedYes
StatusPublished
ID Code54458

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