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Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2.

Publication ,  Journal Article
Shenoy, SK; Modi, AS; Shukla, AK; Xiao, K; Berthouze, M; Ahn, S; Wilkinson, KD; Miller, WE; Lefkowitz, RJ
Published in: Proc Natl Acad Sci U S A
April 21, 2009

Beta-arrestins are multifunctional adaptors that mediate the desensitization, internalization, and some signaling functions of seven-transmembrane receptors (7TMRs). Agonist-stimulated ubiquitination of beta-arrestin2 mediated by the E3 ubiquitin ligase Mdm2 is critical for rapid beta(2)-adrenergic receptor (beta(2)AR) internalization. We now report the discovery that the deubiquitinating enzyme ubiquitin-specific protease 33 (USP33) binds beta-arrestin2 and leads to the deubiquitination of beta-arrestins. USP33 and Mdm2 function reciprocally and favor respectively the stability or lability of the receptor beta-arrestin complex, thus regulating the longevity and subcellular localization of receptor signalosomes. Receptors such as the beta(2)AR, previously shown to form loose complexes with beta-arrestin ("class A") promote a beta-arrestin conformation conducive for binding to the deubiquitinase, whereas the vasopressin V2R, which forms tight beta-arrestin complexes ("class B"), promotes a distinct beta-arrestin conformation that favors dissociation of the enzyme. Thus, USP33-beta-arrestin interaction is a key regulatory step in 7TMR trafficking and signal transmission from the activated receptors to downstream effectors.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

April 21, 2009

Volume

106

Issue

16

Start / End Page

6650 / 6655

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Vasopressins
  • Ubiquitination
  • Ubiquitin-Protein Ligases
  • Ubiquitin Thiolesterase
  • Signal Transduction
  • Receptors, Cell Surface
  • Proto-Oncogene Proteins c-mdm2
  • Protein Transport
  • Protein Binding
 

Citation

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Shenoy, S. K., Modi, A. S., Shukla, A. K., Xiao, K., Berthouze, M., Ahn, S., … Lefkowitz, R. J. (2009). Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2. Proc Natl Acad Sci U S A, 106(16), 6650–6655. https://doi.org/10.1073/pnas.0901083106
Shenoy, Sudha K., Aalok S. Modi, Arun K. Shukla, Kunhong Xiao, Magali Berthouze, Seungkirl Ahn, Keith D. Wilkinson, William E. Miller, and Robert J. Lefkowitz. “Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2.Proc Natl Acad Sci U S A 106, no. 16 (April 21, 2009): 6650–55. https://doi.org/10.1073/pnas.0901083106.
Shenoy SK, Modi AS, Shukla AK, Xiao K, Berthouze M, Ahn S, et al. Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2. Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6650–5.
Shenoy, Sudha K., et al. “Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2.Proc Natl Acad Sci U S A, vol. 106, no. 16, Apr. 2009, pp. 6650–55. Pubmed, doi:10.1073/pnas.0901083106.
Shenoy SK, Modi AS, Shukla AK, Xiao K, Berthouze M, Ahn S, Wilkinson KD, Miller WE, Lefkowitz RJ. Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2. Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6650–6655.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

April 21, 2009

Volume

106

Issue

16

Start / End Page

6650 / 6655

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Vasopressins
  • Ubiquitination
  • Ubiquitin-Protein Ligases
  • Ubiquitin Thiolesterase
  • Signal Transduction
  • Receptors, Cell Surface
  • Proto-Oncogene Proteins c-mdm2
  • Protein Transport
  • Protein Binding