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Engagement of S1P1-degradative mechanisms leads to vascular leak in mice
Myat Lin Oo, … , David K. Han, Timothy Hla
Myat Lin Oo, … , David K. Han, Timothy Hla
Published May 9, 2011
Citation Information: J Clin Invest. 2011;121(6):2290-2300. https://doi.org/10.1172/JCI45403.
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Research Article Cell biology

Engagement of S1P1-degradative mechanisms leads to vascular leak in mice

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Abstract

GPCR inhibitors are highly prevalent in modern therapeutics. However, interference with complex GPCR regulatory mechanisms leads to both therapeutic efficacy and adverse effects. Recently, the sphingosine-1-phosphate (S1P) receptor inhibitor FTY720 (also known as Fingolimod), which induces lymphopenia and prevents neuroinflammation, was adopted as a disease-modifying therapeutic in multiple sclerosis. Although highly efficacious, dose-dependent increases in adverse events have tempered its utility. We show here that FTY720P induces phosphorylation of the C-terminal domain of S1P receptor 1 (S1P1) at multiple sites, resulting in GPCR internalization, polyubiquitinylation, and degradation. We also identified the ubiquitin E3 ligase WWP2 in the GPCR complex and demonstrated its requirement in FTY720-induced receptor degradation. GPCR degradation was not essential for the induction of lymphopenia, but was critical for pulmonary vascular leak in vivo. Prevention of receptor phosphorylation, internalization, and degradation inhibited vascular leak, which suggests that discrete mechanisms of S1P receptor regulation are responsible for the efficacy and adverse events associated with this class of therapeutics.

Authors

Myat Lin Oo, Sung-Hee Chang, Shobha Thangada, Ming-Tao Wu, Karim Rezaul, Victoria Blaho, Sun-Il Hwang, David K. Han, Timothy Hla

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Figure 1

Posttranslational modification of S1P1 after FTY720P treatment.

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Posttranslational modification of S1P1 after FTY720P treatment.
   
(A) ...
(A) Schematic of S1P1 fused with the tandem-affinity construct. CBD, calmodulin-binding domain; Chi-BD, chitin-binding domain. (B) Purification and IB analysis of the S1P1 tandem-affinity construct. (C) Coomassie blue staining of purified S1P1 from HEK293 cells after treatment with vehicle or FTY720P (100 nM for 30 minutes). (D) Schematic diagram of seventh transmembrane domain (TM) and C-terminal tail of S1P1. Shown are the S-palmitoylation sites on cysteine residues (C) as well as phosphorylated serine and ubiquitinylated lysine residues identified by LC/MS/MS. Spectral counts of modified peptides are also shown.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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