TY - JOUR
T1 - A marine sponge-derived lectin reveals hidden pathway for thrombopoietin receptor activation
AU - Watari, Hiromi
AU - Kageyama, Hiromu
AU - Masubuchi, Nami
AU - Nakajima, Hiroya
AU - Onodera, Kako
AU - Focia, Pamela J.
AU - Oshiro, Takumi
AU - Matsui, Takashi
AU - Kodera, Yoshio
AU - Ogawa, Tomohisa
AU - Yokoyama, Takeshi
AU - Hirayama, Makoto
AU - Hori, Kanji
AU - Freymann, Douglas M.
AU - Imai, Misa
AU - Komatsu, Norio
AU - Araki, Marito
AU - Tanaka, Yoshikazu
AU - Sakai, Ryuichi
N1 - Funding Information:
We thank Professor Yasuhiko Kizuka at Gifu University for providing 6-alkynyl fucose and valuable comments. We also thank Dr. Yinjie Yang and Ms. Mai Nudejima for their technical assistances, Dr. Takanori Nakamura at Nissan Chemical Co. Ltd. and Dr. Megumi Funakoshi-Tago at Faculty of Pharmacy, Keio University for providing Ba/F3 cells, the Global Facility Center at Hokkaido University for performing amino acid sequence analysis, the Laboratory of Molecular and Biochemical Research and the Division of Cell Biology in the Research Support Center of the Juntendo University Graduate School of Medicine for their technical assistants for immunoblot and FACS analysis, the Teijin Scholarship Foundation, Suntory Foundation for Life Science and the Japan Society for the Promotion of Science (JSPS) DC2 for scholarships to H.W. Japan Society for the Promotion of Science (JSPS) #19H03040 (R.S.), #22H02430 (R.S.), #21K08376 (M.I.), #21K08405 (N.M.), #21K08424 (N.K.), #19K08848 (M.A.), #22H02252 (Y.T.), #22H02915 (Y.T.), #22K20589 (H.W.), and Grant-in-aid for JSPS fellows #20J11377(H.W.) for fundings. We also thank funding from Ikeda Scientific Co., Ltd (H.W.), the SENSHIN Medical Research Foundation (M.A.) and Takeda Science Foundation (M.A.). We are grateful to Chuuk State Department of Marine Resources for providing permission to collect sponges.
Funding Information:
We thank Professor Yasuhiko Kizuka at Gifu University for providing 6-alkynyl fucose and valuable comments. We also thank Dr. Yinjie Yang and Ms. Mai Nudejima for their technical assistances, Dr. Takanori Nakamura at Nissan Chemical Co. Ltd. and Dr. Megumi Funakoshi-Tago at Faculty of Pharmacy, Keio University for providing Ba/F3 cells, the Global Facility Center at Hokkaido University for performing amino acid sequence analysis, the Laboratory of Molecular and Biochemical Research and the Division of Cell Biology in the Research Support Center of the Juntendo University Graduate School of Medicine for their technical assistants for immunoblot and FACS analysis, the Teijin Scholarship Foundation, Suntory Foundation for Life Science and the Japan Society for the Promotion of Science (JSPS) DC2 for scholarships to H.W. Japan Society for the Promotion of Science (JSPS) #19H03040 (R.S.), #22H02430 (R.S.), #21K08376 (M.I.), #21K08405 (N.M.), #21K08424 (N.K.), #19K08848 (M.A.), #22H02252 (Y.T.), #22H02915 (Y.T.), #22K20589 (H.W.), and Grant-in-aid for JSPS fellows #20J11377(H.W.) for fundings. We also thank funding from Ikeda Scientific Co., Ltd (H.W.), the SENSHIN Medical Research Foundation (M.A.) and Takeda Science Foundation (M.A.). We are grateful to Chuuk State Department of Marine Resources for providing permission to collect sponges.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85142476940&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-34921-2
DO - 10.1038/s41467-022-34921-2
M3 - Article
C2 - 36433967
AN - SCOPUS:85142476940
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 7262
ER -
