Control of type II transforming growth factor-β receptor expression by integrin ligation

Dan Hui Wang, Lu Zhe Sun, Elizabeth Zborowska, James K.V. Willson, Jiangen Gong, Janaki Verraraghavan, Michael G. Brattain

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Ectopic expression of the α5 integrin subunit in cancer cells with little or no endogenous expression of this integrin often results in reduced proliferation as well as reduced malignancy. We now show that inhibition resulting from ectopic expression of α5 integrin is due to induction of autocrine negative transforming growth factor-β (TGF-β) activity. MCF-7 breast cancer cells do not express either α5 integrin or type II TGF-β receptor and hence are unable to generate TGF-β signal transduction. Ectopic expression of α5-integrin expression enhanced cell adhesion to fibronectin, reduced proliferation, and increased the expression of type II TGF-β receptor mRNA and cell surface protein. Receptor expression was increased to a higher level in α5 transfectants by growth on fibronectin-coated plates. Induction of type II TGF-β receptor expression also resulted in the generation of autocrine negative TGF-β activity because colony formation was increased after TGF-β neutralizing antibody treatment. Transient transfection with a TGF-β promoter response element in tandem with a luciferase cDNA into cells stably transfected with α5 integrin resulted in basal promoter activities 5-10-fold higher than those of control cells. Moreover, when α5 transfectants were treated with a neutralizing antibody to either TGF-β or integrin α5, this increased basal promoter activity was blocked. Autocrine TGF-β activity also induced 3-fold higher endogenous fibronectin expression in α5 transfectants relative to that of control cells. Re-expression of type II receptor by α5 transfection also restored the ability of the cells to respond to exogenous TGF-β and led to reduced tumor growth in athymic nude mice. Taken together, these results show for the first time that TGF-β type II receptor expression can be controlled by α5β1 ligation and integrin signal transduction. Moreover, TGF-β and integrin signal transduction appear to cooperate in their tumor-suppressive functions.

Original languageEnglish (US)
Pages (from-to)12840-12847
Number of pages8
JournalJournal of Biological Chemistry
Volume274
Issue number18
DOIs
StatePublished - Apr 30 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Wang, D. H., Sun, L. Z., Zborowska, E., Willson, J. K. V., Gong, J., Verraraghavan, J., & Brattain, M. G. (1999). Control of type II transforming growth factor-β receptor expression by integrin ligation. Journal of Biological Chemistry, 274(18), 12840-12847. https://doi.org/10.1074/jbc.274.18.12840