Integrin β1 signaling is necessary for transforming growth factor-β 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 -meditated EMT involves the stimulation of a number of signaling path. ways 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-P 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-P signaling to the SMAD and AKT pathways, but did not block TGF-beta -mediated p38MAPK activation. Interestingly, blocking integrin beta (1) function inhibited TGF-p-mediated p383LAPK activation and EMT progression. Limiting p38MAPK activity through the expression of a dominant negative-p38MAPK also blocked TGF-p-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.