SUMMARY Cell fusion is essential for fertilization, myotube formation, and inflammation. Macrophages fuse in 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.
A ortic aneurysm predisposes the aorta to dissection or rupture and causes 1% to 2% of deaths in developed countries.1 Thoracic aortic aneurysms and acute aortic dissections (TAADs) that affect young patients result primarily from genetic mutations. 2 The vulnerability of the aortic wall is mainly because of its poor ability to appropriately accommodate hemodynamic changes. The aortic wall, particularly in the thoracic aorta, is able to distend without requiring subsequent contraction of vascular smooth muscle cells (VSMCs) because of the elastic recoil provided by the layers of elastin lamellae.3 These mechanical properties depend on the intimate physical and mechanical connections of differentiated VSMCs with the extracellular matrix (ECM, mostly elastin, and collagen) that they produce and organize, connections that are established through force-dependent adhesion proteins (integrins), and the cytoskeleton (actin and myosin).3 During aortic development, VSMCs differentiate from neural crest and second heart field progenitors and also from mesenchymal progenitors recruited to the nascent endothelial tube; during this process, proper interaction needs to Molecular Medicine© 2015 American Heart Association, Inc. Rationale: Aortic dissection or rupture resulting from aneurysm causes 1% to 2% of deaths in developed countries.These disorders are associated with mutations in genes that affect vascular smooth muscle cell differentiation and contractility or extracellular matrix composition and assembly. However, as many as 75% of patients with a family history of aortic aneurysms do not have an identified genetic syndrome.Objective: To determine the role of the protease MMP17/MT4-MMP in the arterial wall and its possible relevance in human aortic pathology. be established between VSMCs and the ECM. 4 Detailed analysis of pulmonary artery development demonstrated that formation of the vessel wall involves the induction of successive layers of VSMCs and the invasion of the outer layers through the reorientation and radial migration of the inner ones. Methods and Results:5 Transforming growth factor (TGF)-B has been extensively studied as an inducer of VSMC maturation, and more recent studies have identified gradients of platelet-derived growth factor (PDGF)-B and other not-yet identified signals as regulators of VSMC differentiation, providing new insights into artery wall development. 5This intimate connection between VSMCs and the ECM ensures that alterations to one affect the other and can have similar effects on the overall mechanical behavior of the vessel. Thus, TAADs can be caused by mutations that affect VSMC function or that alter ECM composition and assembly.2 For example, Marfan syndrome, a genetic syndrome that predisposes to TAAD, is caused by mutations in the fibrillin-1 (FBN1) gene, which encodes an ECM protein necessary for proper elastin formation, 6 whereas in Loeys-Dietz syndrome, TGFB receptors type 1 and 2 (TGFBR1 and TGFBR2) are mutated, 7 resulting in impeded VSMC differentiation.8 Predispositi...
The mechanism by which proteolytic events translate into biological responses is not well understood. To explore the link of pericellular proteolysis to events relevant to capillary sprouting within the inflammatory context, we aimed at the identification of the collection of substrates of the protease MT1-MMP in endothelial tip cells induced by inflammatory stimuli. We applied quantitative proteomics to endothelial cells (ECs) derived from wild-type and MT1-MMP-null mice to identify the substrate repertoire of this protease in TNF-α-activated ECs. Bioinformatics analysis revealed a combinatorial MT1-MMP proteolytic program, in which combined rather than single substrate processing would determine biological decisions by activated ECs, including chemotaxis, cell motility and adhesion, and vasculature development. MT1-MMP-deficient ECs inefficiently processed several of these substrates (TSP1, CYR61, NID1, and SEM3C), validating the model. This novel concept of MT1-MMP-driven combinatorial proteolysis in angiogenesis might be extendable to proteolytic actions in other cellular contexts.
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