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FROUNT Is a Common Regulator of CCR2 and CCR5 Signaling to Control Directional Migration¹

Etsuko Toda,^2* Yuya Terashima,^2* Tsuyoshi Sato, Kenzo Hirose, Shiro Kanegasaki, and Kouji Matsushima^*

^*Department of Molecular Preventive Medicine, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo, Japan; Central Lab, ECI Inc., Meguro-ku, Tokyo, Japan; and Department of Neurobiology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

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-β), 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Targeted Proteins Research Program (TPRP) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

² E.T. and Y.T. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Kouji Matsushima, Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. E-mail address: koujim{at}m.u-tokyo.ac.jp

⁴ Abbreviations used in this paper: Pro-C, membrane-proximal C-terminal; FNT, FROUNT; HOS, human osteosarcoma; siRNA, small interfering RNA.

⁵ The online version of this article contains supplemental material.