title: Cyclic mechanical stretch decreases cell migration by inhibiting phosphatidylinositol 3-kinase- and focal adhesion kinase-mediated JNK1 activation.
abstract: Epithelial cell migration during wound healing requires coordinated signaling pathways that direct polarization of the leading and trailing ends of the cells, cytoskeletal organization, and remodeling of focal adhesions. These inherently mechanical processes are disrupted by cyclic stretch (CS), but the specific signaling molecules involved in this disruption are not well understood. In this study, we demonstrate that inhibition of phosphatidylinositol 3-kinase (PI3K) or expression of a dominant-negative form of PI3K caused inhibition of airway epithelial cell wound closure. CS caused a sustained decrease in activation of PI3K and inhibited wound healing. Expression of constitutively active PI3K stimulated translocation of Tiam1 to the membrane, increased Rac1 activity, and increased wound healing of airway epithelial cells. Increased Rac1 activity resulted in increased phosphorylation of JNK1. PI3K activation was not regulated by association with focal adhesion kinase. Restoration of efficient cell migration during CS required coexpression of constitutively active PI3K, focal adhesion kinase, and JIP3.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Leena P
authors.initials: LP
authors.lastname: Desai
authors.forename: Steven R
authors.initials: SR
authors.lastname: White
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Waters
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002867:Chromones / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D013314:Stress, Mechanical; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D002867:Chromones; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020662:Guanine Nucleotide Exchange Factors; D048055:Mitogen-Activated Protein Kinase 8; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020830:rac1 GTP-Binding Protein; C087334:TIAM1 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one