Pivotal function for cytoplasmic protein FROUNT in CCR2-mediated monocyte chemotaxis |
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Authors: | Terashima Yuya Onai Nobuyuki Murai Masako Enomoto Masahiko Poonpiriya Vongsakorn Hamada Tsuyoshi Motomura Kazushi Suwa Makiko Ezaki Taichi Haga Tatsuya Kanegasaki Shiro Matsushima Kouji |
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Affiliation: | Department of Molecular Preventive Medicine (and Solution Oriented Research for Science and Technology), Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. |
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Abstract: | Ligation of the chemokine receptor CCR2 on monocytes and macrophages with its ligand CCL2 results in activation of the cascade consisting of phosphatidylinositol-3-OH kinase (PI(3)K), the small G protein Rac and lamellipodium protrusion. We show here that a unique clathrin heavy-chain repeat homology protein, FROUNT, directly bound activated CCR2 and formed clusters at the cell front during chemotaxis. Overexpression of FROUNT amplified the chemokine-elicited PI(3)K-Rac-lamellipodium protrusion cascade and subsequent chemotaxis. Blocking FROUNT function by using a truncated mutant or antisense strategy substantially diminished signaling via CCR2. In a mouse peritonitis model, suppression of endogenous FROUNT markedly prevented macrophage infiltration. Thus, FROUNT links activated CCR2 to the PI(3)K-Rac-lamellipodium protrusion cascade and could be a therapeutic target in chronic inflammatory immune diseases associated with macrophage infiltration. |
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