Nature Immunology
6, 827 - 835 (2005)
Published online: 3 July 2005; | doi:10.1038/ni1222
Pivotal function for cytoplasmic protein FROUNT in CCR2-mediated monocyte chemotaxisYuya Terashima1, 2, Nobuyuki Onai1, Masako Murai1, Masahiko Enomoto1, 2, Vongsakorn Poonpiriya1, Tsuyoshi Hamada3, Kazushi Motomura1, Makiko Suwa3, Taichi Ezaki4, Tatsuya Haga5, Shiro Kanegasaki2
& Kouji Matsushima11
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. 2
Effector Cell Institute in Research Center for Advanced Science and Technology, University of Tokyo, Meguro-ku, Tokyo 153-8904, Japan. 3
Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology, Koutou-ku, Tokyo 135-0064, Japan. 4
Department of Anatomy & Developmental Biology, School of Medicine, Tokyo Women's Medical University, Shinjyuku-ku, Tokyo 162-8666, Japan. 5
Institute for Biomolecular Science, Gakushuin University, Toshima-ku, Tokyo 171-8588, Japan.
Correspondence should be addressed to Kouji Matsushima koujim@m.u-tokyo.ac.jp 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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