MT1-MMP is required for myeloid cell fusion via regulation of Rac1 signaling

13 páginas, 7 figuras -- PAGS nros. 77-89Cell fusion is essential for fertilization, myotube formation, and inflammation. Macrophages fuse under various circumstances, but the molecular signals involved in the distinct steps of their fusion are not fully characterized. Using null mice and derived cells, we show that the protease MT1-MMP is necessary for macrophage fusion during osteoclast and giant-cell formation in vitro and in vivo. Specifically, MT1-MMP is required for lamellipodia formation and for proper cell morphology and motility of bone marrow myeloid progenitors prior to membrane fusion. These functions of MT1-MMP do not depend on MT1-MMP catalytic activity or downstream pro-MMP-2 activation. Instead, MT1-MMP null cells show a decreased Rac1 activity and reduced membrane targeting of Rac1 and the adaptor protein p130Cas. Retroviral rescue experiments and protein binding assays delineate a signaling pathway in which MT1-MMP, via its cytosolic tail, contributes to macrophage migration and fusion by regulating Rac1 activity through an association with p130CasThis work was supported by National Institutes of Health grant AR47074 (to S.S.A.), the Fundación Ramón Areces and Spanish Fondo de Investigación Sanitaria grant RD06/0014/1016 (to A.G.A.), the Spanish Ministry of Science and Innovation through grants SAF2008-02100 to M.A.d.P. and SAF2008-02104 to A.G.A., and EUROHORCS (European Heads of Research Councils) and the European Science Foundation (ESF) through a EURYI (European Young Investigator) award to M.A.d.P. P.G. was funded by the Juan de la Cierva program and the Fondo de Investigación Sanitaria. M.C.G. and M.V.H.-R. are supported by fellowships BES-2006-13204 and 12790 from the Spanish Ministry of Science and Innovation, respectively. The CNIC is supported by the Spanish Ministry of Science and Innovation and the Pro-CNIC Foundation. J.R. is one of the inventors of the ICTP assay, but the royalty period has expiredPeer reviewe