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Cell Growth & Differentiation Vol. 10, 11-18, January 1999
© 1999 American Association for Cancer Research

Differential Responsiveness to Autocrine and Exogenous Transforming Growth Factor (TGF) ß1 in Cells with Nonfunctional TGF-ß Receptor Type III1

Xiaobing Deng, Susan Bellis, Zhongfa Yan and Eileen Friedman2

State University of New York Health Science Center, Syracuse, New York 13210

The two major intestinal epithelial cell lineages are columnar fluid-absorbing cells and mucin-producing goblet cells. High levels of transforming growth factor (TGF) ß1 are found surrounding postmitotic cells in the colonic crypt, suggesting that TGF-ß1 mediates the maturation and growth inhibition of both epithelial cell types. However, we now show that the injection of recombinant TGF-ß1 into mice leads to an enrichment of goblet cells, indicating that these normal epithelial cells are resistant to TGF-ß1. In support of this interpretation, each of two independently isolated cell lines modeling normal colon goblet cells was also growth resistant to exogenous TGF-ß1 but made levels of TGF-ß receptor (TßR) I, TßRII, and TßIII mRNA and protein equal to those made by two TGF-ß1-sensitive cell lines. No mutations were found in the alk5 or alk2 forms of TßRI or in TßRII; these receptors were found on the cell surface, although they could not bind 125I-labeled TGF-ß1. TßRIII binds TGF-ß1, concentrates it, and presents it to TßRII. The major TßRIII form, betaglycan, did not undergo normal posttranslational modification in either of the goblet cell lines and could not bind 125I-labeled TGF-ß1; thus, it was nonfunctional. TGF-ß resistance was overcome by raising TGF-ß1 levels 100-fold, at which point TßRII could bind TGF-ß1. Signaling initiated by these higher TGF-ß1 levels was blocked by the expression of dominant negative TßRII, demonstrating that TßRII and TßRI were functional. Cells resistant to exogenous TGF-ß1 maintained functional cell surface TßRI and TßRII to mediate responses to autocrine TGF-ß1, which controlled the maturation of the adhesion protein integrin ß1. Expression of dominant negative TßRII in goblet cells greatly inhibited the conversion of the ß1 integrin from its precursor to its mature form. Thus, in normal intestinal epithelial goblet cells, TßRI and TßRII can respond to autocrine but not exogenous TGF-ß without the participation of TßRIII. Absorptive epithelial cells are growth inhibited by TGF-ß1 both in vivo and in vitro; therefore, the loss of functional TßRIIIs on goblet cells allows differential regulation of the two major intestinal epithelial cell types.




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation
Copyright © 1999 by the American Association of Cancer Research.