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A marine sponge-derived lectin reveals hidden pathway for thrombopoietin receptor activation

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Title: A marine sponge-derived lectin reveals hidden pathway for thrombopoietin receptor activation
Authors: Watari, Hiromi Browse this author →KAKEN DB
Kageyama, Hiromu Browse this author
Masubuchi, Nami Browse this author →KAKEN DB
Nakajima, Hiroya Browse this author
Onodera, Kako Browse this author
Focia, Pamela J. Browse this author
Oshiro, Takumi Browse this author
Matsui, Takashi Browse this author →KAKEN DB
Kodera, Yoshio Browse this author →KAKEN DB
Ogawa, Tomohisa Browse this author →KAKEN DB
Yokoyama, Takeshi Browse this author →KAKEN DB
Hirayama, Makoto Browse this author →KAKEN DB
Hori, Kanji Browse this author →KAKEN DB
Freymann, Douglas M. Browse this author
Imai, Misa Browse this author →KAKEN DB
Komatsu, Norio Browse this author →KAKEN DB
Araki, Marito Browse this author →KAKEN DB
Tanaka, Yoshikazu Browse this author →KAKEN DB
Sakai, Ryuichi Browse this author →KAKEN DB
Issue Date: 2023
Publisher: Nature Portfolio
Journal Title: Nature communications
Volume: 13
Issue: 1
Start Page: 7262
Publisher DOI: 10.1038/s41467-022-34921-2
Abstract: The mode of cytokine receptor activation is diverse. Here, the authors find that the marine-sponge derived lectin ThC, a bivalent sugar binding protein, activates human cytokine receptor MPL. This mode of action resembles the pathogenic activation of MPL by mutant molecular chaperon calreticulin in hematologic malignancies. N-glycan-mediated activation of the thrombopoietin receptor (MPL) under pathological conditions has been implicated in myeloproliferative neoplasms induced by mutant calreticulin, which forms an endogenous receptor-agonist complex that traffics to the cell surface and constitutively activates the receptor. However, the molecular basis for this mechanism is elusive because oncogenic activation occurs only in the cell-intrinsic complex and is thus cannot be replicated with external agonists. Here, we describe the structure and function of a marine sponge-derived MPL agonist, thrombocorticin (ThC), a homodimerized lectin with calcium-dependent fucose-binding properties. In-depth characterization of lectin-induced activation showed that, similar to oncogenic activation, sugar chain-mediated activation persists due to limited receptor internalization. The strong synergy between ThC and thrombopoietin suggests that ThC catalyzes the formation of receptor dimers on the cell surface. Overall, the existence of sugar-mediated MPL activation, in which the mode of activation is different from the original ligand, suggests that receptor activation is unpredictably diverse in living organisms.
Type: article
Appears in Collections:水産科学院・水産科学研究院 (Graduate School of Fisheries Sciences / Faculty of Fisheries Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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