Ligand-induced tyrosine phosphorylation of cysteinyl leukotriene receptor 1 triggers internalization and signaling in intestinal epithelial cells.

<h4>Background</h4>Leukotriene D(4) (LTD(4)) belongs to the bioactive lipid group known as eicosanoids and has implications in pathological processes such as inflammation and cancer. Leukotriene D(4) exerts its effects mainly through two different G-protein-coupled receptors, CysLT(1) an...

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Autores principales: Ladan Parhamifar, Wondossen Sime, Yuliana Yudina, Frederik Vilhardt, Matthias Mörgelin, Anita Sjölander
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spelling oai:doaj.org-article:2593142dbc78474f9adb0162f902233c2021-11-18T07:01:10ZLigand-induced tyrosine phosphorylation of cysteinyl leukotriene receptor 1 triggers internalization and signaling in intestinal epithelial cells.1932-620310.1371/journal.pone.0014439https://doaj.org/article/2593142dbc78474f9adb0162f902233c2010-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21203429/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Leukotriene D(4) (LTD(4)) belongs to the bioactive lipid group known as eicosanoids and has implications in pathological processes such as inflammation and cancer. Leukotriene D(4) exerts its effects mainly through two different G-protein-coupled receptors, CysLT(1) and CysLT(2). The high affinity LTD(4) receptor CysLT(1)R exhibits tumor-promoting properties by triggering cell proliferation, survival, and migration in intestinal epithelial cells. In addition, increased expression and nuclear localization of CysLT(1)R correlates with a poorer prognosis for patients with colon cancer.<h4>Methodology/principal findings</h4>Using a proximity ligation assay and immunoprecipitation, this study showed that endogenous CysLT(1)R formed heterodimers with its counter-receptor CysLT(2)R under basal conditions and that LTD(4) triggers reduced dimerization of CysLTRs in intestinal epithelial cells. This effect was dependent upon a parallel LTD(4)-induced increase in CysLT(1)R tyrosine phosphorylation. Leukotriene D(4) also led to elevated internalization of CysLT(1)Rs from the plasma membrane and a simultaneous increase at the nucleus. Using sucrose, a clathrin endocytic inhibitor, dominant-negative constructs, and siRNA against arrestin-3, we suggest that a clathrin-, arrestin-3, and Rab-5-dependent process mediated the internalization of CysLT(1)R. Altering the CysLT(1)R internalization process at either the clathrin or the arrestin-3 stage led to disruption of LTD(4)-induced Erk1/2 activation and up-regulation of COX-2 mRNA levels.<h4>Conclusions/significance</h4>Our data suggests that upon ligand activation, CysLT(1)R is tyrosine-phosphorylated and released from heterodimers with CysLT(2)R and, subsequently, internalizes from the plasma membrane to the nuclear membrane in a clathrin-, arrestin-3-, and Rab-5-dependent manner, thus, enabling Erk1/2 signaling and downstream transcription of the COX-2 gene.Ladan ParhamifarWondossen SimeYuliana YudinaFrederik VilhardtMatthias MörgelinAnita SjölanderPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 12, p e14439 (2010)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Ladan Parhamifar
Wondossen Sime
Yuliana Yudina
Frederik Vilhardt
Matthias Mörgelin
Anita Sjölander
Ligand-induced tyrosine phosphorylation of cysteinyl leukotriene receptor 1 triggers internalization and signaling in intestinal epithelial cells.
description <h4>Background</h4>Leukotriene D(4) (LTD(4)) belongs to the bioactive lipid group known as eicosanoids and has implications in pathological processes such as inflammation and cancer. Leukotriene D(4) exerts its effects mainly through two different G-protein-coupled receptors, CysLT(1) and CysLT(2). The high affinity LTD(4) receptor CysLT(1)R exhibits tumor-promoting properties by triggering cell proliferation, survival, and migration in intestinal epithelial cells. In addition, increased expression and nuclear localization of CysLT(1)R correlates with a poorer prognosis for patients with colon cancer.<h4>Methodology/principal findings</h4>Using a proximity ligation assay and immunoprecipitation, this study showed that endogenous CysLT(1)R formed heterodimers with its counter-receptor CysLT(2)R under basal conditions and that LTD(4) triggers reduced dimerization of CysLTRs in intestinal epithelial cells. This effect was dependent upon a parallel LTD(4)-induced increase in CysLT(1)R tyrosine phosphorylation. Leukotriene D(4) also led to elevated internalization of CysLT(1)Rs from the plasma membrane and a simultaneous increase at the nucleus. Using sucrose, a clathrin endocytic inhibitor, dominant-negative constructs, and siRNA against arrestin-3, we suggest that a clathrin-, arrestin-3, and Rab-5-dependent process mediated the internalization of CysLT(1)R. Altering the CysLT(1)R internalization process at either the clathrin or the arrestin-3 stage led to disruption of LTD(4)-induced Erk1/2 activation and up-regulation of COX-2 mRNA levels.<h4>Conclusions/significance</h4>Our data suggests that upon ligand activation, CysLT(1)R is tyrosine-phosphorylated and released from heterodimers with CysLT(2)R and, subsequently, internalizes from the plasma membrane to the nuclear membrane in a clathrin-, arrestin-3-, and Rab-5-dependent manner, thus, enabling Erk1/2 signaling and downstream transcription of the COX-2 gene.
format article
author Ladan Parhamifar
Wondossen Sime
Yuliana Yudina
Frederik Vilhardt
Matthias Mörgelin
Anita Sjölander
author_facet Ladan Parhamifar
Wondossen Sime
Yuliana Yudina
Frederik Vilhardt
Matthias Mörgelin
Anita Sjölander
author_sort Ladan Parhamifar
title Ligand-induced tyrosine phosphorylation of cysteinyl leukotriene receptor 1 triggers internalization and signaling in intestinal epithelial cells.
title_short Ligand-induced tyrosine phosphorylation of cysteinyl leukotriene receptor 1 triggers internalization and signaling in intestinal epithelial cells.
title_full Ligand-induced tyrosine phosphorylation of cysteinyl leukotriene receptor 1 triggers internalization and signaling in intestinal epithelial cells.
title_fullStr Ligand-induced tyrosine phosphorylation of cysteinyl leukotriene receptor 1 triggers internalization and signaling in intestinal epithelial cells.
title_full_unstemmed Ligand-induced tyrosine phosphorylation of cysteinyl leukotriene receptor 1 triggers internalization and signaling in intestinal epithelial cells.
title_sort ligand-induced tyrosine phosphorylation of cysteinyl leukotriene receptor 1 triggers internalization and signaling in intestinal epithelial cells.
publisher Public Library of Science (PLoS)
publishDate 2010
url https://doaj.org/article/2593142dbc78474f9adb0162f902233c
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