Cellular interactions with the extracellular matrix are coupled to diverse transmembrane signaling pathways.
Extracellular matrix (ECM) glycoproteins such as laminin, fibronectin, or collagen IV play a major role in cell behavior regulation. The molecular mechanisms taking place at the interface between the ECM and the cell surface are now rather well defined; however, very little is known about intracellular signals induced by these interactions. In order to get insights into the transduction pathways involved in cell-ECM interactions we have investigated the effects of several intracellular kinase inhibitors. Calmodulin-dependent kinase inhibitors, W-7 and sphingosine, have negative effects on cell-matrix interactions. They inhibit adhesion of several cell lines to laminin (IC50 = 4-10 microM), fibronectin and collagen IV (IC50 = 7-25 microM). The effects are immediate, reversible, and also cell specific, certain combinations of cell line-substrate being irresponsive to these inhibitors. In contrast, two inhibitors, H-7 and staurosporine, for which protein kinase C is a common target, increase two- to fourfold the attachment of HT1080, OVCAR-4, and B16F10 cells to laminin but not to fibronectin. Another inhibitor, HA-1004, known to inhibit protein kinase A at low concentrations, has an activating effect only at high concentration (> 200 microM) when it becomes an inhibitor of protein kinase C. These inhibitors are without effect on RuGli and Saos-2 cell adhesion on the three substrates. Altogether these results suggest that calmodulin-dependent kinases and protein kinase C could be separately involved in ECM-induced cellular responses. However, the effects of kinase inhibitors are substrate-specific and cell type-specific, suggesting that the intracellular signals induced by the extracellular matrix vary with the nature of integrin involved in signal transmission.
Gimond
C
C
Institut de Biologie et Chimie des Protéines, Centre National de la Recherche Scientifique, UPR 412, Lyon, France.
Aumailley
M
M
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002147:Calmodulin / Q000494:pharmacology; D002448:Cell Adhesion; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007797:Laminin / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D019311:Staurosporine; D013449:Sulfonamides; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D002147:Calmodulin; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D007546:Isoquinolines; D007797:Laminin; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D003094:Collagen; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D011494:Protein Kinases; D011493:Protein Kinase C; D019311:Staurosporine