Emerging Roles of β-Arrestins

Buchanan, F. Gregory; DuBois, Raymond N.

doi:10.4161/cc.5.18.3212

Cited by 34 publications

(28 citation statements)

References 41 publications

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“…More specifically, ␤-arrestin2 has been linked to cancer metastasis through its regulation of p38 activity. Decreased cancer cell metastasis has been demonstrated previously in HeLa and human embryonic kidney 293 cells that have reduced ␤-arrestin2 levels (50). Association of ␤-arrestin2 with T␤RIII could lead to down-regulation of ␤-arrestin2 and, therefore, a decrease in cell motility, which we have observed in T␤RIII expressing prostate, lung, and breast cancer cell lines in vitro (15,17,20).…”

Section: Discussionsupporting

confidence: 77%

Endocytosis of the Type III Transforming Growth Factor-β (TGF-β) Receptor through the Clathrin-independent/Lipid Raft Pathway Regulates TGF-β Signaling and Receptor Down-regulation

Finger

Lee

You

et al. 2008

Journal of Biological Chemistry

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Transforming growth factor-␤ (TGF-␤) signals through three highly conserved cell surface receptors, the type III TGF-␤ receptor (T␤RIII), the type II TGF-␤ receptor (T␤RII), and the type I TGF-␤ receptor (T␤RI) to regulate diverse cellular processes including cell proliferation, differentiation, migration, and apoptosis. Although T␤RI and T␤RII undergo ligand-independent endocytosis by both clathrin-mediated endocytosis, resulting in enhanced signaling, and clathrin-independent endocytosis, resulting in receptor degradation, the mechanism and function of T␤RIII endocytosis is poorly understood. T␤RIII is a heparan sulfate proteoglycan with a short cytoplasmic tail that functions as a TGF-␤ superfamily co-receptor, contributing to TGF-␤ signaling through mechanisms yet to be fully defined. We have reported previously that T␤RIII endocytosis, mediated by a novel interaction with ␤arrestin-2, results in decreased TGF-␤ signaling. Here we demonstrate that T␤RIII undergoes endocytosis in a ligand and glycosaminoglycan modification-independent and cytoplasmic domain-dependent manner, with the interaction of Thr-841 in the cytoplasmic domain of T␤RIII with ␤-arrestin2 enhancing T␤RIII endocytosis. T␤RIII undergoes both clathrin-mediated and clathrin-independent endocytosis. Importantly, inhibition of the clathrin-independent, lipid raft pathway, but not of the clathrin-dependent pathway, results in decreased TGF-␤1 induced Smad2 and p38 phosphorylation, supporting a specific role for clathrin-independent endocytosis of T␤RIII in regulating both Smad-dependent and Smad-independent TGF-␤ signaling.The TGF-␤ 2 superfamily is composed of more than 30 polypeptide growth factors, including the bone morphogenetic proteins and activins, which regulate cell proliferation, differentiation, adhesion, angiogenesis, and embryonic development (1-4). Three highly conserved and tissue-specific TGF-␤ isoforms signal through heteromeric complexes of three cell surface receptors, the type III TGF-␤ receptor (T␤RIII, or betaglycan), the type II TGF-␤ receptor (T␤RII), and the type I TGF-␤ receptor (T␤RI). Although T␤RII and T␤RI are both transmembrane serine/threonine kinase receptors, T␤RIII is a heparan sulfate proteoglycan with a short cytoplasmic tail that fundamentally contributes to TGF-␤ signaling through mechanisms yet to be defined. T␤RIII binds all three forms of TGF-␤ ligands specifically; T␤RII binds TGF-␤1 and TGF-␤3 independently, whereas T␤RI cannot bind ligand on its own. Upon ligand binding, the constitutively active T␤RII recruits T␤RI into an active heterotetrameric signaling complex composed of two T␤RIs and two T␤RIIs and transphosphorylates the glycine and serine rich region of T␤RI to activate its kinase function (5). T␤RI can then phosphorylate C-terminal serine residues on transcription factors known as Smads, specifically the receptorSmads, Smad2 and Smad3, which then associate with the common-Smad, Smad4 (6). This association allows accumulation of the complex into the nucleus and transcription of target genes. ...

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Section: Discussionsupporting

confidence: 77%

Endocytosis of the Type III Transforming Growth Factor-β (TGF-β) Receptor through the Clathrin-independent/Lipid Raft Pathway Regulates TGF-β Signaling and Receptor Down-regulation

Finger

Lee

You

et al. 2008

Journal of Biological Chemistry

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“…It is now increasingly apparent that, in addition to their regulatory functions, ␤-arrs may also represent signaling adaptors connecting GPCRs, as well as receptors of other families, to a growing number of effector pathways (reviewed in refs. [5][6][7][8]. Although most functions of ␤-arrs depend on their interactions with molecular partners at the plasma or endosomal membranes, ␤-arrs also have biological roles within the nucleus.…”

mentioning

confidence: 99%

β-arrestin 2 oligomerization controls the Mdm2-dependent inhibition of p53

Boularan

Scott

Bourougaa

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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␤-arrestins (␤-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 ␤-arrs are believed to interact with receptors after agonist activation, and therefore, ␤-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 ␤-arr2 oligomers together with the previously characterized nucleocytoplasmic shuttling of ␤-arr2. Mutation of the IP6-binding sites impair oligomerization, reduce interaction with Mdm2, and inhibit p53-dependent antiproliferative effects of ␤-arr2, whereas the competence for receptor regulation and signaling is maintained. These observations suggest that the intracellular concentration of ␤-arr2 oligomers might control cell survival and proliferation. bioluminescence resonance energy transfer ͉ FRET ͉ nucleocytoplasmic shuttling ͉ ubiquitination

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“…Earlier studies indicate that ␤-arrestins associate with GPCRs, which mediates receptor endocytosis, and also function as adaptors linking GPCRs to intracellular signaling pathways (10)(11)(12)(13)(14)(15)(16). More recently, it has been shown that ␤-arrestins can bind to IB␣, leading to suppressed NF-B activation induced by TNF␣, IL-1␤, and UV light (20)(21)(22)(23).…”

Section: Resultsmentioning

confidence: 99%

“…␤-Arrestins belong to a family of adaptor proteins that were initially considered as components to desensitize GPCR activation. However, more recent studies indicate that ␤-arrestins are also involved in mediating GPCR-induced signal transduction (10)(11)(12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

β-Arrestin 2 is required for lysophosphatidic acid-induced NF-κB activation

Sun

Lin

2008

Proc. Natl. Acad. Sci. U.S.A.

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Lysophosphatidic acid (LPA) is a bioactive phospholipid and binds to its receptors, a family of G protein-coupled receptors (GPCR), which initiates multiple signaling cascades and leads to activation of several transcription factors, including NF-B. Although LPA-induced signaling pathways have been intensively investigated, the molecular mechanism by which LPA activates NF-B is not fully defined. In this work, we found that ␤-arrestin 2, but not ␤-arrestin 1, is required for LPA-induced NF-B activation and interlukin-6 expression. Mechanistically, we found that ␤-arrestin 2 associated with CARMA3, a scaffold protein that plays an essential role in GPCR-induced NF-B activation, suggesting that ␤-arrestin 2 may recruit CARMA3 to LPA receptors. Although ␤-arrestin 2 deficiency did not affect LPA-induced IKK␣/␤ phosphorylation, it impaired LPA-induced IKK kinase activity, which is consistent with our previous findings that CARMA3 is required for IKK␣/␤ activation but not for the inducible phosphorylation of IKK␣/␤. Together, our results provide the genetic evidence that ␤-arrestin 2 serves as a positive regulator in NF-B signaling pathway by connecting CARMA3 to GPCRs.CARMA3 ͉ G protein-coupled receptor ͉ IKK

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Emerging Roles of β-Arrestins

Cited by 34 publications

References 41 publications

Endocytosis of the Type III Transforming Growth Factor-β (TGF-β) Receptor through the Clathrin-independent/Lipid Raft Pathway Regulates TGF-β Signaling and Receptor Down-regulation

Endocytosis of the Type III Transforming Growth Factor-β (TGF-β) Receptor through the Clathrin-independent/Lipid Raft Pathway Regulates TGF-β Signaling and Receptor Down-regulation

β-arrestin 2 oligomerization controls the Mdm2-dependent inhibition of p53

β-Arrestin 2 is required for lysophosphatidic acid-induced NF-κB activation

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