Pivotal function for cytoplasmic protein FROUNT in CCR2-mediated monocyte chemotaxis

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 homolog...

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Bibliographic Details
Published in:Nature Immunology 2005-08, Vol.6 (8), p.827-835
Main 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
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Biomedical and Life Sciences
Biomedicine
Bone Marrow Cells - cytology
Cell Line
Cell Membrane - metabolism
Chemotaxis
Clathrin Heavy Chains - biosynthesis
Clathrin Heavy Chains - physiology
Cloning, Molecular
Cytoplasm - metabolism
DNA, Complementary - metabolism
Dose-Response Relationship, Drug
Glutathione Transferase - metabolism
Humans
Immunohistochemistry
Immunology
Infectious Diseases
Infiltration
Inflammation
Ligands
Macrophages - cytology
Macrophages - immunology
Macrophages - metabolism
Mice
Mice, Inbred C57BL
Microscopy, Fluorescence
Molecular Sequence Data
Monocytes - cytology
Mutation
Nuclear Pore Complex Proteins
Peptides - chemistry
Peritonitis - metabolism
Phosphatidylinositol 3-Kinases - metabolism
Protein Transport
Pseudopodia - metabolism
Receptors, CCR2
Receptors, Chemokine - chemistry
Retroviridae - genetics
Sequence Analysis, DNA
Sequence Homology, Amino Acid
Signal Transduction
Subcellular Fractions - metabolism
Time Factors
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Summary: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.
ISSN:1529-2908
1529-2916
1365-2567
DOI:10.1038/ni1222