Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity.
Transforming growth factor-beta (TGF-beta) can induce epithelial to mesenchymal transdifferentiation (EMT) in mammary epithelial cells. TGF-beta-mediated EMT involves the stimulation of a number of signaling pathways by the sequential binding of the type II and type I serine/threonine kinase receptors, respectively. Integrins comprise a family of heterodimeric extracellular matrix receptors that mediate cell adhesion and intracellular signaling, hence making them crucial for EMT progression. In light of substantial evidence indicating TGF-beta regulation of various beta(1) integrins and their extracellular matrix ligands, we examined the cross-talk between the TGF-beta and integrin signal transduction pathways. Using an inducible system for the expression of a cytoplasmically truncated dominant negative TGF-beta type II receptor, we blocked TGF-beta-mediated growth inhibition, transcriptional activation, and EMT progression. Dominant negative TGF-beta type II receptor expression inhibited TGF-beta signaling to the SMAD and AKT pathways, but did not block TGF-beta-mediated p38MAPK activation. Interestingly, blocking integrin beta(1) function inhibited TGF-beta-mediated p38MAPK activation and EMT progression. Limiting p38MAPK activity through the expression of a dominant negative-p38MAPK also blocked TGF-beta-mediated EMT. In summary, TGF-beta-mediated p38MAPK activation is dependent on functional integrin beta(1), and p38MAPK activity is required but is not sufficient to induce EMT.
Bhowmick
N A
NA
Vanderbilt-Ingram Cancer Center, Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Zent
R
R
Ghiassi
M
M
McDonnell
M
M
Moses
H L
HL
D002448:Cell Adhesion; D002454:Cell Differentiation; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004441:Ecdysterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005799:Genes, Dominant; D015151:Immunoblotting; D019012:Integrin beta1 / Q000378:metabolism*; D008024:Ligands; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013050:Spectrometry, Fluorescence; D013997:Time Factors; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D018076:DNA, Complementary; D019012:Integrin beta1; D008024:Ligands; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D004441:Ecdysterone; C008999:ponasterone A; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II