TGF-beta1-mediated activations of c-Src and Rac1 modulate levels of cyclins and p27(Kip1) CDK inhibitor in hepatoma cells replated on fibronectin.
Integrin-mediated cell adhesion transduces signals to regulate actin cytoskeleton and cell proliferation. While understanding how integrin signals cross-talk with the TGF-beta1 pathways, we observed lamellipodia formation and cyclin regulation in Hep3B cells, following TGF-beta1 treatment. To answer if integrin signaling via actin organization might regulate cell cycle progression after TGF-beta1 treatment, we analyzed cross-talk between the two receptor-mediated pathways in hepatoma cells on specific ECMs. We found that basal and TGF-beta1-mediated activation of c-Src and Rac1, expression of cyclins E and A, and suppression of p27Kip1 were significant in cells replated on fibronectin, but not in cells on collagen I, indicating a different integrin-mediated cellular response to TGF-beta1 treatment. Levels of tyrosine phosphorylation and actin-enriched lamellipodia on fibronectin were also more prominent than in cells on collagen I. Studies using pharmacological inhibitors or transient transfections revealed that the preferential TGF-beta1 effects in cells on fibronectin required c-Src family kinase activity. These observations suggest that a specific cross-talk between TGF-beta1 and fibronectin-binding integrin signal pathways leads to the activation of c-Src/Rac1/actin-organization, leading to changes in cell cycle regulator levels in hepatoma cells. Therefore, this study represents another mechanism to regulate cell cycle regulators when integrin signaling is collaborative with TGF-beta1 pathways.
Kim
Hwang-Phill
HP
National Research Laboratory for Cancer Epigenetics, Cancer Research Institute, Department of Tumor Biology, College of Medicine, Seoul National University, Seoul 110-799, South Korea.
Kim
Tai-Young
TY
Lee
Mi-Sook
MS
Jong
Hyun-Soon
HS
Kim
Tae-You
TY
Lee
Jung Weon
JW
Bang
Yung-Jue
YJ
D000199:Actins / Q000378:metabolism; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002448:Cell Adhesion; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D024042:Collagen Type I / Q000378:metabolism; D019925:Cyclin A / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003599:Cytoskeleton; D004591:Electrophoresis, Polyacrylamide Gel; D005353:Fibronectins / Q000378:metabolism*; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D005786:Gene Expression Regulation; D006801:Humans; D039421:Integrin alpha2 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D008858:Microscopy, Phase-Contrast; D009154:Mutation; D010770:Phosphotransferases / Q000378:metabolism*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D019061:src-Family Kinases
D000199:Actins; D018797:Cell Cycle Proteins; D024042:Collagen Type I; D019925:Cyclin A; D019927:Cyclin E; D005353:Fibronectins; D039421:Integrin alpha2; D016023:Integrins; D011518:Proto-Oncogene Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D010770:Phosphotransferases; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D020830:rac1 GTP-Binding Protein; D001973:Bromodeoxyuridine