The effect of arrestin conformation on the recruitment of c-Raf1, MEK1, and ERK1/2 activation.

Arrestins are multifunctional signaling adaptors originally discovered as proteins that "arrest" G protein activation by G protein-coupled receptors (GPCRs). Recently GPCR complexes with arrestins have been proposed to activate G protein-independent signaling pathways. In particular, arres...

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Autores principales:	Sergio Coffa, Maya Breitman, Susan M Hanson, Kari Callaway, Seunghyi Kook, Kevin N Dalby, Vsevolod V Gurevich
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fb428791600a42a187f3913576941165
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spelling	oai:doaj.org-article:fb428791600a42a187f39135769411652021-11-18T07:32:31ZThe effect of arrestin conformation on the recruitment of c-Raf1, MEK1, and ERK1/2 activation.1932-620310.1371/journal.pone.0028723https://doaj.org/article/fb428791600a42a187f39135769411652011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22174878/?tool=EBIhttps://doaj.org/toc/1932-6203Arrestins are multifunctional signaling adaptors originally discovered as proteins that "arrest" G protein activation by G protein-coupled receptors (GPCRs). Recently GPCR complexes with arrestins have been proposed to activate G protein-independent signaling pathways. In particular, arrestin-dependent activation of extracellular signal-regulated kinase 1/2 (ERK1/2) has been demonstrated. Here we have performed in vitro binding assays with pure proteins to demonstrate for the first time that ERK2 directly binds free arrestin-2 and -3, as well as receptor-associated arrestins-1, -2, and -3. In addition, we showed that in COS-7 cells arrestin-2 and -3 association with β(2)-adrenergic receptor (β2AR) significantly enhanced ERK2 binding, but showed little effect on arrestin interactions with the upstream kinases c-Raf1 and MEK1. Arrestins exist in three conformational states: free, receptor-bound, and microtubule-associated. Using conformationally biased arrestin mutants we found that ERK2 preferentially binds two of these: the "constitutively inactive" arrestin-Δ7 mimicking microtubule-bound state and arrestin-3A, a mimic of the receptor-bound conformation. Both rescue arrestin-mediated ERK1/2/activation in arrestin-2/3 double knockout fibroblasts. We also found that arrestin-2-c-Raf1 interaction is enhanced by receptor binding, whereas arrestin-3-c-Raf1 interaction is not.Sergio CoffaMaya BreitmanSusan M HansonKari CallawaySeunghyi KookKevin N DalbyVsevolod V GurevichPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 12, p e28723 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sergio Coffa Maya Breitman Susan M Hanson Kari Callaway Seunghyi Kook Kevin N Dalby Vsevolod V Gurevich The effect of arrestin conformation on the recruitment of c-Raf1, MEK1, and ERK1/2 activation.
description	Arrestins are multifunctional signaling adaptors originally discovered as proteins that "arrest" G protein activation by G protein-coupled receptors (GPCRs). Recently GPCR complexes with arrestins have been proposed to activate G protein-independent signaling pathways. In particular, arrestin-dependent activation of extracellular signal-regulated kinase 1/2 (ERK1/2) has been demonstrated. Here we have performed in vitro binding assays with pure proteins to demonstrate for the first time that ERK2 directly binds free arrestin-2 and -3, as well as receptor-associated arrestins-1, -2, and -3. In addition, we showed that in COS-7 cells arrestin-2 and -3 association with β(2)-adrenergic receptor (β2AR) significantly enhanced ERK2 binding, but showed little effect on arrestin interactions with the upstream kinases c-Raf1 and MEK1. Arrestins exist in three conformational states: free, receptor-bound, and microtubule-associated. Using conformationally biased arrestin mutants we found that ERK2 preferentially binds two of these: the "constitutively inactive" arrestin-Δ7 mimicking microtubule-bound state and arrestin-3A, a mimic of the receptor-bound conformation. Both rescue arrestin-mediated ERK1/2/activation in arrestin-2/3 double knockout fibroblasts. We also found that arrestin-2-c-Raf1 interaction is enhanced by receptor binding, whereas arrestin-3-c-Raf1 interaction is not.
format	article
author	Sergio Coffa Maya Breitman Susan M Hanson Kari Callaway Seunghyi Kook Kevin N Dalby Vsevolod V Gurevich
author_facet	Sergio Coffa Maya Breitman Susan M Hanson Kari Callaway Seunghyi Kook Kevin N Dalby Vsevolod V Gurevich
author_sort	Sergio Coffa
title	The effect of arrestin conformation on the recruitment of c-Raf1, MEK1, and ERK1/2 activation.
title_short	The effect of arrestin conformation on the recruitment of c-Raf1, MEK1, and ERK1/2 activation.
title_full	The effect of arrestin conformation on the recruitment of c-Raf1, MEK1, and ERK1/2 activation.
title_fullStr	The effect of arrestin conformation on the recruitment of c-Raf1, MEK1, and ERK1/2 activation.
title_full_unstemmed	The effect of arrestin conformation on the recruitment of c-Raf1, MEK1, and ERK1/2 activation.
title_sort	effect of arrestin conformation on the recruitment of c-raf1, mek1, and erk1/2 activation.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/fb428791600a42a187f3913576941165
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The effect of arrestin conformation on the recruitment of c-Raf1, MEK1, and ERK1/2 activation.

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