Abstract

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.