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 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 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.
authors.affiliation: Stress Response Laboratory, Division of Cancer Research, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Kidger
authors.affiliation: Stress Response Laboratory, Division of Cancer Research, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Rushworth
authors.affiliation: Stress Response Laboratory, Division of Cancer Research, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom.
authors.forename: Julia
authors.initials: J
authors.lastname: Stellzig
authors.affiliation: Stress Response Laboratory, Division of Cancer Research, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Davidson
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bryant
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom.
authors.forename: Cassidy
authors.initials: C
authors.lastname: Bayley
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom.
authors.forename: Edward
authors.initials: E
authors.lastname: Caddye
authors.affiliation: Centre for Networks and Collective Behaviour, Department of Mathematical Sciences, University of Bath, Bath BA2 7AY, United Kingdom.
authors.forename: Tim
authors.initials: T
authors.lastname: Rogers
authors.affiliation: Stress Response Laboratory, Division of Cancer Research, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom; c.caunt@bath.ac.uk s.m.keyse@dundee.ac.uk.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Keyse
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom; c.caunt@bath.ac.uk s.m.keyse@dundee.ac.uk.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Caunt
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D054637:Dual-Specificity Phosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D048490:raf Kinases / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D054637:Dual-Specificity Phosphatases; C546197:Dusp5 protein, mouse
keywords: DUSP; ERK; MAPK; MKP; signaling