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PMID: 15173580 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

beta-Arrestin inhibits NF-kappaB activity by means of its interaction with the NF-kappaB inhibitor IkappaBalpha.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 23 ·2004-06-08 ·Pages 8603-7

Witherow DS, Garrison TR, Miller WE, Lefkowitz RJ

Abstract

In addition to their roles in desensitization and signaling of seven-membrane-spanning receptors, beta-arrestins have been more recently implicated in regulating non-seven-membrane-spanning receptor pathways. By using a yeast two-hybrid screen, we identified the inhibitor of NF-kappaB, IkappaBalpha, as a binding partner of beta-arrestin 1. Both beta-arrestin 1 and 2 interact with IkappaBalpha in transfected cells as assessed by immunoprecipitation experiments. Additionally, upstream kinases known to regulate the function of IkappaBalpha, such as IkappaB kinase alpha and beta and NF-kappaB-inducing kinase, were also shown to interact with beta-arrestin. Overexpression of either beta-arrestin 1 or beta-arrestin 2 led to marked inhibition of NF-kappaB activity, as measured by reporter gene activity. Inhibition of NF-kappaB activity was independent of the type of stimulus used for NF-kappaB activation. Conversely, suppression of beta-arrestin 1, but not beta-arrestin 2, expression by using RNA interference led to a 3-fold increase in tumor necrosis factor-stimulated NF-kappaB activity as measured by NF-kappaB mobility-shift analysis. These data uncover a role of beta-arrestins in the regulation of NF-kappaB-mediated gene regulation.

MeSH Terms
Arrestins/genetics,metabolism,pharmacology HeLa Cells Humans I-kappa B Proteins/metabolism In Vitro Techniques NF-KappaB Inhibitor alpha NF-kappa B/antagonists & inhibitors,metabolism RNA Interference RNA, Small Interfering/genetics,metabolism Recombinant Fusion Proteins/genetics,metabolism,pharmacology Transfection Two-Hybrid System Techniques beta-Arrestin 1 beta-Arrestin 2 beta-Arrestins
Chemicals
ARRB1 protein, human ARRB2 protein, human Arrestins I-kappa B Proteins NF-kappa B NFKBIA protein, human RNA, Small Interfering Recombinant Fusion Proteins beta-Arrestin 1 beta-Arrestin 2 beta-Arrestins NF-KappaB Inhibitor alpha
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Witherow D Scott
Department of Medicine and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Garrison Tiffany Runyan
Miller William E
Lefkowitz Robert J
References (40)
40 references, click to expand
  1. Beta-arrestin2, a novel member of the arrestin/beta-arrestin gene family.
    J Biol Chem. 1992 Sep 5;267(25):17882-90 PMID: 1517224
  2. Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B.
    Proc Natl Acad Sci U S A. 1989 Apr;86(7):2336-40 PMID: 2494664
  3. A proteasome inhibitor prevents activation of NF-kappa B and stabilizes a newly phosphorylated form of I kappa B-alpha that is still bound to NF-kappa B.
    EMBO J. 1994 Nov 15;13(22):5433-41 PMID: 7957109
  4. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation.
    Science. 1995 Mar 10;267(5203):1485-8 PMID: 7878466
  5. Protein-tyrosine phosphatase inhibitors block tumor necrosis factor-dependent activation of the nuclear transcription factor NF-kappa B.
    J Biol Chem. 1995 May 5;270(18):10631-9 PMID: 7738000
  6. Studies on the transformation of intact yeast cells by the LiAc/SS-DNA/PEG procedure.
    Yeast. 1995 Apr 15;11(4):355-60 PMID: 7785336
  7. Phosphorylation of human I kappa B-alpha on serines 32 and 36 controls I kappa B-alpha proteolysis and NF-kappa B activation in response to diverse stimuli.
    EMBO J. 1995 Jun 15;14(12):2876-83 PMID: 7796813
  8. Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway.
    Genes Dev. 1995 Jul 1;9(13):1586-97 PMID: 7628694
  9. The NF-kappa B and I kappa B proteins: new discoveries and insights.
    Annu Rev Immunol. 1996;14:649-83 PMID: 8717528
  10. Tyrosine phosphorylation of I kappa B-alpha activates NF-kappa B without proteolytic degradation of I kappa B-alpha.
    Cell. 1996 Sep 6;86(5):787-98 PMID: 8797825
  11. Genomic libraries and a host strain designed for highly efficient two-hybrid selection in yeast.
    Genetics. 1996 Dec;144(4):1425-36 PMID: 8978031
  12. The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism.
    Cell. 1997 May 2;89(3):413-24 PMID: 9150141
  13. Identification and characterization of an IkappaB kinase.
    Cell. 1997 Jul 25;90(2):373-83 PMID: 9244310
  14. Tumor necrosis factor (TNF)-mediated kinase cascades: bifurcation of nuclear factor-kappaB and c-jun N-terminal kinase (JNK/SAPK) pathways at TNF receptor-associated factor 2.
    Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9792-6 PMID: 9275204
  15. Synergistic activation of NF-kappaB by tumor necrosis factor alpha and gamma interferon via enhanced I kappaB alpha degradation and de novo I kappaBbeta degradation.
    Mol Cell Biol. 1997 Nov;17(11):6746-54 PMID: 9343439
  16. IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK.
    Science. 1997 Oct 31;278(5339):866-9 PMID: 9346485
  17. IkappaBbeta interacts with the retinoid X receptor and inhibits retinoid-dependent transactivation in lipopolysaccharide-treated cells.
    J Biol Chem. 1998 Feb 6;273(6):3212-5 PMID: 9452433
  18. The role of receptor kinases and arrestins in G protein-coupled receptor regulation.
    Annu Rev Pharmacol Toxicol. 1998;38:289-319 PMID: 9597157
  19. Molecular mechanisms of G protein-coupled receptor signaling: role of G protein-coupled receptor kinases and arrestins in receptor desensitization and resensitization.
    Receptors Channels. 1997;5(3-4):193-9 PMID: 9606723
  20. G protein-coupled receptors. III. New roles for receptor kinases and beta-arrestins in receptor signaling and desensitization.
    J Biol Chem. 1998 Jul 24;273(30):18677-80 PMID: 9668034
  21. Feedback regulation of beta-arrestin1 function by extracellular signal-regulated kinases.
    J Biol Chem. 1999 Jun 4;274(23):15971-4 PMID: 10347142
  22. Carbachol activates IkappaB kinase in isolated canine gastric parietal cells.
    Biochem Biophys Res Commun. 1999 Aug 11;261(3):877-84 PMID: 10441519
  23. A subclass of Ras proteins that regulate the degradation of IkappaB.
    Science. 2000 Feb 4;287(5454):869-73 PMID: 10657303
  24. Tumor necrosis factor-alpha activation of the IL-2 receptor-alpha gene involves the induction of kappa B-specific DNA binding proteins.
    J Immunol. 1989 May 1;142(9):3121-8 PMID: 2785134
  25. Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat.
    Proc Natl Acad Sci U S A. 1989 Aug;86(15):5974-8 PMID: 2762307
  26. beta-Arrestin: a protein that regulates beta-adrenergic receptor function.
    Science. 1990 Jun 22;248(4962):1547-50 PMID: 2163110
  27. Characterization of an immediate-early gene induced in adherent monocytes that encodes I kappa B-like activity.
    Cell. 1991 Jun 28;65(7):1281-9 PMID: 1829648
  28. beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2.
    J Cell Biol. 2000 Mar 20;148(6):1267-81 PMID: 10725339
  29. beta-arrestin1 interacts with the catalytic domain of the tyrosine kinase c-SRC. Role of beta-arrestin1-dependent targeting of c-SRC in receptor endocytosis.
    J Biol Chem. 2000 Apr 14;275(15):11312-9 PMID: 10753943
  30. Tyrosine phosphorylation-dependent activation of NF-kappa B. Requirement for p56 LCK and ZAP-70 protein tyrosine kinases.
    Eur J Biochem. 2001 Mar;268(5):1508-15 PMID: 11231305
  31. Activation of NF-kappa B is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes.
    Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6668-73 PMID: 11381115
  32. Regulation of nuclear factor kappaB activation by G-protein-coupled receptors.
    J Leukoc Biol. 2001 Dec;70(6):839-48 PMID: 11739545
  33. beta-Arrestin1 modulates lymphoid enhancer factor transcriptional activity through interaction with phosphorylated dishevelled proteins.
    Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14889-94 PMID: 11742073
  34. Arresting developments in heptahelical receptor signaling and regulation.
    Trends Cell Biol. 2002 Mar;12(3):130-8 PMID: 11859025
  35. The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals.
    J Cell Sci. 2002 Feb 1;115(Pt 3):455-65 PMID: 11861753
  36. beta-Arrestin scaffolding of the ERK cascade enhances cytosolic ERK activity but inhibits ERK-mediated transcription following angiotensin AT1a receptor stimulation.
    J Biol Chem. 2002 Mar 15;277(11):9429-36 PMID: 11777902
  37. Desensitization, internalization, and signaling functions of beta-arrestins demonstrated by RNA interference.
    Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1740-4 PMID: 12582207
  38. Beta-arrestin1 mediates insulin-like growth factor 1 (IGF-1) activation of phosphatidylinositol 3-kinase (PI3K) and anti-apoptosis.
    J Biol Chem. 2003 Dec 19;278(51):51334-9 PMID: 14534298
  39. I kappa B: a specific inhibitor of the NF-kappa B transcription factor.
    Science. 1988 Oct 28;242(4878):540-6 PMID: 3140380
  40. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B.
    Cell. 1994 Sep 9;78(5):773-85 PMID: 8087845
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0402851101
Published
2004-06-08
Epub
2004-00-01
Pages
8603-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC423241
Subset
IM
Grants
NHLBI NIH HHS · R01 HL016037 · United States
NHLBI NIH HHS · R01 HL16037 · United States
External Links
PubMed source DOI: 10.1073/pnas.0402851101 PMC Full Text View journal details
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