FROUNT is a common regulator of CCR2 and CCR5 signaling to control directional migration.
FROUNT is a known CCR2-binding protein that facilitates monocyte/macrophage infiltration. Here we report that FROUNT also binds to the C-terminal region of CCR5 and enhances CCR5-mediated cellular chemotaxis. We show that FROUNT overexpression enhances the directionality of chemotaxis, while FROUNT suppression results in impaired responsiveness. Furthermore, we found an increase in consolidated pseudopodium formation in FROUNT-overexpressing cells (FNT cells) on uniform stimulation with CCL4 (MIP1-beta), a specific ligand of CCR5. In most FNT cells, one to two pseudopodia directed toward higher chemokine concentration were found, whereas most FNT-suppressed cells had multiple pseudopodia. The data indicate that FROUNT is involved in sensing and amplifying a shallow extracellular chemokine gradient that leads to a limited number of accurate pseudopodia directed toward the chemokine concentration. In addition to its separate roles in CCR2- and CCR5-mediated chemotaxis, FROUNT, as a common regulator of these receptors, possibly plays a crucial role in the recruitment of immune cells expressing these receptors.
Department of Molecular Preventive Medicine, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Etsuko
E
Toda
Yuya
Y
Terashima
Tsuyoshi
T
Sato
Kenzo
K
Hirose
Shiro
S
Kanegasaki
Kouji
K
Matsushima
D000199:Actins / Q000276:immunology / Q000378:metabolism; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D054407:Chemokine CCL4 / Q000494:pharmacology; D002633:Chemotaxis; D006801:Humans; D008969:Molecular Sequence Data; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010802:Phylogeny; D011554:Pseudopodia / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000276:immunology / Q000378:metabolism; D054390:Receptors, CCR2 / Q000276:immunology* / Q000378:metabolism; D019713:Receptors, CCR5 / Q000276:immunology* / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000276:immunology; D014162:Transfection
D000199:Actins; C515334:CCR2 protein, human; D054407:Chemokine CCL4; C503214:NUP85 protein, human; D028861:Nuclear Pore Complex Proteins; D034741:RNA, Small Interfering; D054390:Receptors, CCR2; D019713:Receptors, CCR5