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

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

Research output: Contribution to journalArticle

  • 7 Citations

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.

LanguageEnglish
PagesE317-E326
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number3
Early online date4 Jan 2017
DOIs
StatusPublished - 17 Jan 2017

Fingerprint

Dual-Specificity Phosphatases
Extracellular Signal-Regulated MAP Kinases
Phosphotransferases
Cell Proliferation
Cell Aging
Oncogenes

Keywords

  • DUSP
  • ERK
  • MAPK
  • MKP
  • Signaling

Cite this

Kidger, A. M., Rushworth, L. K., Stellzig, J., Davidson, J., Bryant, C. J., Bayley, C., ... Caunt, C. J. (2017). Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling. DOI: 10.1073/pnas.1614684114

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

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 3, 17.01.2017, p. E317-E326.

Research output: Contribution to journalArticle

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./ Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 3. pp. E317-E326
@article{0b24593cf7f6442bb23fd2385427b482,
title = "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 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.",
keywords = "DUSP, ERK, MAPK, MKP, Signaling",
author = "Kidger, {Andrew M.} and Rushworth, {Linda K.} and Julia Stellzig and Jane Davidson and Bryant, {Christopher J.} and Cassidy Bayley and Edward Caddye and Tim Rogers and Keyse, {Stephen M.} and Caunt, {Christopher J.}",
year = "2017",
month = "1",
day = "17",
doi = "10.1073/pnas.1614684114",
language = "English",
volume = "114",
pages = "E317--E326",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "Proceedings of the National Academy of Sciences",
number = "3",

}

TY - JOUR

T1 - Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling

AU - Kidger,Andrew M.

AU - Rushworth,Linda K.

AU - Stellzig,Julia

AU - Davidson,Jane

AU - Bryant,Christopher J.

AU - Bayley,Cassidy

AU - Caddye,Edward

AU - Rogers,Tim

AU - Keyse,Stephen M.

AU - Caunt,Christopher J.

PY - 2017/1/17

Y1 - 2017/1/17

N2 - 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.

AB - 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.

KW - DUSP

KW - ERK

KW - MAPK

KW - MKP

KW - Signaling

UR - http://www.scopus.com/inward/record.url?scp=85009727885&partnerID=8YFLogxK

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

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

U2 - 10.1073/pnas.1614684114

DO - 10.1073/pnas.1614684114

M3 - Article

VL - 114

SP - E317-E326

JO - Proceedings of the National Academy of Sciences of the United States of America

T2 - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 3

ER -