Epithelial cells utilize cortical actin/myosin to activate latent TGF-β through integrin α(v)β(6)-dependent physical force.
Transforming Growth Factor Beta (TGF-β) is involved in regulating many biological processes and disease states. Cells secrete cytokine as a latent complex that must be activated for it to exert its biological functions. We previously discovered that the epithelial-restricted integrin α(v)β(6) activates TGF-β and that this process is important in a number of in vivo models of disease. Here, we show that agonists of G-protein coupled receptors (Sphingosine-1-Phosphate and Lysophosphatidic Acid) which are ligated under conditions of epithelial injury directly stimulate primary airway epithelial cells to activate latent TGF-β through a pathway that involves Rho Kinase, non-muscle myosin, the α(v)β(6) integrin, and the generation of mechanical tension. Interestingly, lung epithelial cells appear to exert force on latent TGF-β using sub-cortical actin/myosin rather than the stress fibers utilized by fibroblasts and other traditionally "contractile" cells. These findings extend recent evidence suggesting TGF-β can be activated by integrin-mediated mechanical force and suggest that this mechanism is important for an integrin (α(v)β(6)) and a cell type (epithelial cells) that have important roles in biologically relevant TGF-β activation in vivo.
Lung Biology Center, Department of Medicine, University of California, San Francisco, CA, USA.
Marilyn M
MM
Giacomini
Mark A
MA
Travis
Makoto
M
Kudo
Dean
D
Sheppard
D000199:Actins / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000378:metabolism*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism; D009218:Myosins / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D000199:Actins; D000951:Antigens, Neoplasm; D016023:Integrins; D008246:Lysophospholipids; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6; C060506:sphingosine 1-phosphate; D009218:Myosins; D013110:Sphingosine; C032881:lysophosphatidic acid