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

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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