beta-arrestin 2 oligomerization controls the Mdm2-dependent inhibition of p53.
beta-arrestins (beta-arrs), two ubiquitous proteins involved in serpentine heptahelical receptor regulation and signaling, form constitutive homo- and heterooligomers stabilized by inositol 1,2,3,4,5,6-hexakisphosphate (IP6). Monomeric beta-arrs are believed to interact with receptors after agonist activation, and therefore, beta-arr oligomers have been proposed to represent a resting biologically inactive state. In contrast to this, we report here that the interaction with and subsequent titration out of the nucleus of the protooncogene Mdm2 specifically require beta-arr2 oligomers together with the previously characterized nucleocytoplasmic shuttling of beta-arr2. Mutation of the IP6-binding sites impair oligomerization, reduce interaction with Mdm2, and inhibit p53-dependent antiproliferative effects of beta-arr2, whereas the competence for receptor regulation and signaling is maintained. These observations suggest that the intracellular concentration of beta-arr2 oligomers might control cell survival and proliferation.
Boularan
Cédric
C
Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (Unité Mixte de Recherche 8104), 75014 Paris, France.
Scott
Mark G H
MG
Bourougaa
Karima
K
Bellal
Myriam
M
Esteve
Emmanuel
E
Thuret
Alain
A
Benmerah
Alexandre
A
Tramier
Marc
M
Coppey-Moisan
Maité
M
Labbé-Jullié
Catherine
C
Fåhraeus
Robin
R
Marullo
Stefano
S
D000818:Animals; D019390:Arrestins / Q000737:chemistry / Q000502:physiology*; D001665:Binding Sites; D001704:Biopolymers / Q000737:chemistry*; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D010833:Phytic Acid / Q000378:metabolism / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605254:ARRB2 protein, human; D019390:Arrestins; D001704:Biopolymers; D016159:Tumor Suppressor Protein p53; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D010833:Phytic Acid; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2