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J. Biol. Chem., Vol. 276, Issue 50, 46707-46713, December 14, 2001
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From the Transforming growth factor-
Integrin
1 Signaling Is Necessary for Transforming
Growth Factor- Activation of p38MAPK and Epithelial
Plasticity*
,§,,, and¶
Vanderbilt-Ingram Cancer Center, Department
of Cancer Biology and the § Department of Medicine,
Vanderbilt University Medical Center, Nashville, Tennessee 37232
(TGF-) can
induce epithelial to mesenchymal transdifferentiation (EMT) in mammary
epithelial cells. TGF--meditated 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- regulation of various
1 integrins and their extracellular matrix
ligands, we examined the cross-talk between the TGF- and integrin
signal transduction pathways. Using an inducible system for the
expression of a cytoplasmically truncated dominant negative TGF-
type II receptor, we blocked TGF--mediated growth inhibition,
transcriptional activation, and EMT progression. Dominant negative
TGF- type II receptor expression inhibited TGF- signaling to the
SMAD and AKT pathways, but did not block TGF--mediated p38MAPK
activation. Interestingly, blocking integrin 1 function
inhibited TGF--mediated p38MAPK activation and EMT progression.
Limiting p38MAPK activity through the expression of a dominant
negative-p38MAPK also blocked TGF--mediated EMT. In summary,
TGF--mediated p38MAPK activation is dependent on functional integrin
1, and p38MAPK activity is required but is not
sufficient to induce EMT.
*
This work was supported by a Department of Defense US
Army Medical Research and Materiel Command Grant BC991184 (to
N. A. B.), National Kidney Foundation Young Investigator Grant
(to R. Z.), Public Health Service Grants CA42572 and CA85492 (to
H. L. M.), and Vanderbilt-Ingram Cancer Center Support Grant CA68485. Fluorescence microscopy images were acquired through the use of the
Vanderbilt University Medical Center Cell Imaging Core Resource, (supported by National Institutes of Health Grants CA68485 and DK20593).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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