Cytoskeletal reorganization leads to induction of the urokinase-type plasminogen activator gene by activating FAK and Src and subsequently the Ras/Erk signaling pathway.
Previously, we showed that cytoskeletal reorganization (CSR) induced by colchicine or cyochalasins leads to activation of the urokinase-type plasminogen activator (uPA) gene in LLC-PK(1) cells via the Ras/Erk signaling pathway [Irigoyen et al. (1997) J. Biol. Chem. 272, 1904]. It remained to be seen how CSR activates Ras/Erk signaling. Changes in cell morphology triggered by extracellular signals are often mediated by integrin-associated proteins, such as focal adhesion kinase (FAK) and Src. We found that CSR induced the activation of FAK and Src and the association of FAK and Shc, a signaling molecule linking growth factor receptor tyrosine kinase and Grb2. Furthermore, expression of either FRNK, a kinase-minus FAK-like molecule acting as a dominant negative FAK, or a dominant negative Src suppressed CSR-induced uPA gene promoter activation. These results suggest that cells respond to a morphology change, using the cytoskeleton as a sensor, by activating FAK and Src and subsequently the Ras/Erk signaling pathway.
Irigoyen
J P
JP
Friedrich Miescher Institute, Basel, CH-4058, Switzerland.
Nagamine
Y
Y
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D003078:Colchicine / Q000494:pharmacology; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D004790:Enzyme Induction; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics*; D018631:ras Proteins / Q000378:metabolism; D018909:src Homology Domains
D015815:Cell Adhesion Molecules; D015638:Cytochalasin D; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D014568:Urokinase-Type Plasminogen Activator; D018631:ras Proteins; D013755:Tetradecanoylphorbol Acetate; D003078:Colchicine