MT1-MMP is required for myeloid cell fusion via regulation of Rac1 signaling.
Cell 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 p130Cas.
Gonzalo
Pilar
P
Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain.
Guadamillas
Marta C
MC
Hernández-Riquer
María Victoria
MV
Pollán
Angela
A
Grande-García
Araceli
A
Bartolomé
Rubén A
RA
Vasanji
Amit
A
Ambrogio
Chiara
C
Chiarle
Roberto
R
Teixidó
Joaquín
J
Risteli
Juha
J
Apte
Suneel S
SS
del Pozo
Miguel A
MA
Arroyo
Alicia G
AG
D000818:Animals; D016723:Bone Remodeling / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002459:Cell Fusion; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002465:Cell Movement / Q000502:physiology; D048430:Cell Shape / Q000502:physiology; D002478:Cells, Cultured; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D015726:Giant Cells / Q000378:metabolism / Q000648:ultrastructure; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D011554:Pseudopodia / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
C493842:Bcar1 protein, mouse; D050719:Crk-Associated Substrate Protein; D053511:Matrix Metalloproteinase 14; D020830:rac1 GTP-Binding Protein