Journal of Biological Chemistry
Volume 278, Issue 5, 31 January 2003, Pages 3275-3285
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MECHANISMS OF SIGNAL TRANSDUCTION
Autocrine Transforming Growth Factor-β Signaling Mediates Smad-independent Motility in Human Cancer Cells*

https://doi.org/10.1074/jbc.M204623200Get rights and content
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Transforming growth factor-β (TGF-β) is a pleiotropic growth factor that plays a critical role in modulating cell growth, differentiation, and plasticity. There is increasing evidence that after cells lose their sensitivity to TGF-β-mediated growth inhibition, autocrine TGF-β signaling may potentially promote tumor cell motility and invasiveness. To understand the molecular mechanisms by which autocrine TGF-β may selectively contribute to tumor cell motility, we have generated MDA-MB-231 breast cancer cells stably expressing a kinase-inactive type II TGF-β receptor (TβRII-K277R). Our data indicate that TβRII-K277R is expressed, can associate with the type I TGF-β receptor, and block both Smad-dependent and -independent signaling pathways activated by TGF-β. In addition, wound closure and transwell migration assays indicated that the basal migratory potential of TβRII-K277R expressing cells was impaired. The impaired motility of TβRII-K277R cells could be restored by reconstituting TGF-β signaling with a constitutively active TGF-β type I receptor (ALK5TD) but not by reconstituting Smad signaling with Smad2/4 or Smad3/4 expression. In addition, the levels of ALK5TD expression sufficient to restore motility in the cells expressing TβRII-K277R were associated with an increase in phosphorylation of Akt and extracellular signal-regulated kinase 1/2 but not Smad2. These data indicate that different signaling pathways require different thresholds of TGF-β activation and suggest that TGF-β promotes motility through mechanisms independent of Smad signaling, possibly involving activation of the phosphatidylinositol 3-kinase/Akt and/or mitogen-activated protein kinase pathways.

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Published, JBC Papers in Press, November 5, 2002, DOI 10.1074/jbc.M204623200

*

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. This work was supported in part by United States Army Medical Research and Materiel Command Awards DAMD17-98-1-8263 (to N. D.), BC011342 (to A. V. B.), and DAMD17-98-1-8262 (to C. L. A.), by Public Health Service Grants CA62212 (to C. L. A.) and CA95263 (to A. V. B.), and by Vanderbilt-Ingram Cancer Center Support Grant CA68485.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.