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Agonist-promoted Ubiquitination Differentially Regulates Receptor Trafficking of Endothelin Type A and Type B Receptors

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Title: Agonist-promoted Ubiquitination Differentially Regulates Receptor Trafficking of Endothelin Type A and Type B Receptors
Authors: Terada, Koji Browse this author →KAKEN DB
Horinouchi, Takahiro Browse this author →KAKEN DB
Fujioka, Yoichiro Browse this author
Higashi, Tsunehito Browse this author →KAKEN DB
Nepal, Prabha Browse this author
Horiguchi, Mika Browse this author
Karki, Sarita Browse this author
Hatate, Chizuru Browse this author
Hoshi, Akimasa Browse this author
Harada, Takuya Browse this author
Mai, Yosuke Browse this author
Ohba, Yusuke Browse this author →KAKEN DB
Miwa, Soichi Browse this author →KAKEN DB
Keywords: Endocytosis
Issue Date: 19-Dec-2014
Publisher: American Society for Biochemistry and Molecular Biology (ASBMB)
Journal Title: Journal of biological chemistry
Volume: 289
Issue: 51
Start Page: 35283
End Page: 35295
Publisher DOI: 10.1074/jbc.M113.544171
Abstract: Two types of G protein-coupled receptors for endothelin-1 (ET-1), ET type A receptor (ETAR) and ETBR, closely resemble each other, but upon ET-1 stimulation, they follow totally different intracellular trafficking pathways; ETAR is recycled back to plasma membrane, whereas ETBR is targeted to lysosome for degradation. However, the mechanisms for such different fates are unknown. Here we demonstrated that ETBR but not ETAR was ubiquitinated on the cell surface following ET-1 stimulation and that ETBR was internalized and degraded in lysosome more rapidly than ETAR. The mutant ETBR (designated 5KR mutant) in which 5 lysine residues in the C-tail were substituted to arginine was not ubiquitinated, and its rates of internalization and degradation after ET-1 stimulation became slower, being comparable with those of ETAR. Confocal microscopic study showed that following ET-1 stimulation, ETAR and 5KR mutant of ETBR were co-localized mainly with Rab11, a marker of recycling endosome, whereas ETBR was co-localized with Rab7, a marker of late endosome/lysosome. In the 5KR mutant, ET-1-induced ERK phosphorylation and an increase in the intracellular Ca2+ concentration upon repetitive ET-1 stimulation were larger. A series of ETBR mutants (designated 4KR mutant), in which either one of 5 arginine residues of the 5KR mutant was reverted to lysine, were normally ubiquitinated, internalized, and degraded, with ERK phosphorylation being normalized. These results demonstrate that agonist-induced ubiquitination at either lysine residue in the C-tail of ETBR but not ETAR switches intracellular trafficking from recycling to plasma membrane to targeting to lysosome, causing decreases in the cell surface level of ETBR and intracellular signaling.
Rights: This research was originally published in [Koji Terada, et al. "Agonist-promoted Ubiquitination Differentially Regulates Receptor Trafficking of Endothelin Type A and Type B Receptors" The Journal of Biological Chemistry, 289(51), 2014, pp.35283-35295]. © the American Society for Biochemistry and Molecular Biology.
Type: article (author version)
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 三輪 聡一

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