Boularan Cédric, Scott Mark G H, Bourougaa Karima, Bellal Myriam, Esteve Emmanuel, Thuret Alain, Benmerah Alexandre, Tramier Marc, Coppey-Moisan Maité, Labbé-Jullié Catherine, Fåhraeus Robin, Marullo Stefano
Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (Unité Mixte de Recherche 8104), 75014 Paris, France.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18061-6. doi: 10.1073/pnas.0705550104. Epub 2007 Nov 5.
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.
β-抑制蛋白（β-arrs）是两种普遍存在的蛋白质，参与七螺旋蛇形受体的调节和信号传导，它们形成由肌醇六磷酸（IP6）稳定的组成型同型和异型寡聚体。单体β-arrs被认为在激动剂激活后与受体相互作用，因此，有人提出β-arr寡聚体代表一种静止的生物学非活性状态。与此相反，我们在此报告，与原癌基因Mdm2的核相互作用以及随后将其从核中滴定出来特别需要β-arr2寡聚体，以及先前已表征的β-arr2的核质穿梭。IP6结合位点的突变会损害寡聚化，减少与Mdm2的相互作用，并抑制β-arr2的p53依赖性抗增殖作用，而受体调节和信号传导能力则得以维持。这些观察结果表明，β-arr2寡聚体的细胞内浓度可能控制细胞存活和增殖。
