Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity

J Biol Chem. 2001 Dec 14;276(50):46707-13. doi: 10.1074/jbc.M106176200. Epub 2001 Oct 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Adhesion
  • Cell Differentiation
  • Cytoplasm / metabolism
  • DNA, Complementary / metabolism
  • Dose-Response Relationship, Drug
  • Ecdysterone / analogs & derivatives*
  • Ecdysterone / pharmacology
  • Enzyme Activation
  • Epithelial Cells / enzymology
  • Epithelial Cells / metabolism
  • Extracellular Matrix / metabolism
  • Genes, Dominant
  • Immunoblotting
  • Integrin beta1 / metabolism*
  • Ligands
  • Mesoderm / cytology
  • Mesoderm / metabolism
  • Microscopy, Fluorescence
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phenotype
  • Phosphorylation
  • Precipitin Tests
  • Protein Binding
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction*
  • Spectrometry, Fluorescence
  • Time Factors
  • Transcriptional Activation
  • Transforming Growth Factor beta / metabolism*
  • p38 Mitogen-Activated Protein Kinases


  • DNA, Complementary
  • Integrin beta1
  • Ligands
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Ecdysterone
  • ponasterone A
  • Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Receptor, Transforming Growth Factor-beta Type II