| 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 |
| URI: | http://hdl.handle.net/2115/87775 |
| 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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