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- Title
Pivotal function for cytoplasmic protein FROUNT in CCR2-mediated monocyte chemotaxis.
- 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
- 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.
- Subjects
CHEMOTAXIS; MONOCYTES; LEUCOCYTES; KILLER cells; MEMBRANE proteins; HOMOLOGY (Biology); PERITONEUM diseases
- Publication
Nature Immunology, 2005, Vol 6, Issue 8, p827
- ISSN
1529-2908
- Publication type
Article
- DOI
10.1038/ni1222