title: Fluid shear stress promotes proprotein convertase-dependent activation of MT1-MMP.
abstract: During angiogenesis, endothelial cells (ECs(1)) initiate new blood vessel growth and invade into the extracellular matrix (ECM). Membrane type-1 matrix metalloproteinase (MT1-MMP) facilitates this process and translocates to the plasma membrane following activation to promote ECM cleavage. The N-terminal pro-domain within MT1-MMP must be processed for complete activity of the proteinase. This study investigated whether MT1-MMP activation was altered by sphingosine 1-phosphate (S1P) and wall shear stress (WSS), which combine to stimulate EC invasion in three dimensional (3D) collagen matrices. MT1-MMP was activated rapidly and completely by WSS but not S1P. Proprotein convertases (PCs) promoted MT1-MMP processing, prompting us to test whether WSS or S1P treatments increased PC activity. Like MT1-MMP, PC activity increased with WSS, while S1P had no effect. A pharmacological PC inhibitor completely blocked S1P- and WSS-induced EC invasion and MT1-MMP translocation to the plasma membrane. Further, a recombinant PC inhibitor reduced MT1-MMP activation and decreased lumen formation in invading ECs, a process known to be controlled by MT1-MMP. Thus, we conclude that PC and MT1-MMP activation are mechanosensitive events that are required for EC invasion into 3D collagen matrices.
authors: Molecular & Cellular Medicine, Texas A&M Health Science Center, College Station, TX, USA.
authors: Hojin
authors: H
authors: Kang
authors: Molecular & Cellular Medicine, Texas A&M Health Science Center, College Station, TX, USA.
authors: Camille L
authors: CL
authors: Duran
authors: Molecular & Cellular Medicine, Texas A&M Health Science Center, College Station, TX, USA.
authors: Colette A
authors: CA
authors: Abbey
authors: Department of Biomedical Engineering, Texas A&M University, College Station, TX, USA.
authors: Roland R
authors: RR
authors: Kaunas
authors: Molecular & Cellular Medicine, Texas A&M Health Science Center, College Station, TX, USA. Electronic address: kbayless@medicine.tamhsc.edu.
authors: Kayla J
authors: KJ
authors: Bayless
mesh_terms: D004789:Enzyme Activation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D043484:Proprotein Convertases / Q000378:metabolism*; D013314:Stress, Mechanical
chemical_list: D043484:Proprotein Convertases; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: Angiogenesis; Furin; Mechanotransduction; Sprouting