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.
Mesh Terms:
Animals, Arrestins, Binding Sites, Biopolymers, COS Cells, Cell Line, Cercopithecus aethiops, Humans, Phytic Acid, Proto-Oncogene Proteins c-mdm2, Tumor Suppressor Protein p53
Proc. Natl. Acad. Sci. U.S.A.
Date: Nov. 13, 2007
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