Role of receptor complexes in resistance or sensitivity to growth inhibition by TGFβ in intestinal epithelial cell clones

Untransformed rat intestinal epithelial cells (IEC‐18) were chemically mutagenized, selected in the presence of TGFβ₁, and cloned by limiting dilution. Two clones (4–5, 4–6) were resistant to growth inhibition by both TGFβ₁ and TGFβ₂. Another clone (4–1) was more sensitive to both TGFβ isoforms (relative to parental IEC‐18 cells). IC₅₀ values for TGFβ_{1 and 2} in the 4–1 cells were at least 1/9 those of the parental cells; growth rates were reduced by 49% for TGFβ₁ and by 26% for TGFβ₂ in this clone. This increased sensitivity to TGFβ was explained by the 5‐ to 10‐fold increase, relative to parental cells, in binding of TGFβ₁ and TGFβ₂ to both the type I and II receptors. In contrast, the resistance to growth inhibition by TGFβ in the 4–5 and 4–6 cells could not be explained by a decrease in either TGFβ binding affinities or in total number of receptors expressed, by the presence of serum binding components, or by occupation of receptor binding sites with autocrine TGF‐β₁. However, in comparison to TGFβ‐sensitive cells (IEC‐18, 4–1), the resistant cells displayed a higher ratio of type II relative to type I receptor binding by TGF‐β₁. Thus, a critical ratio of binding to receptor subtypes correlated with growth inhibition by TGF‐β₁. Resistance to TGF‐β₂ in the same clones did not appear to be receptor related. Thus different mechanisms for resistance to TGF‐β₁ and TGF‐β₂ were observed within a given clone. © 1993 Wiley‐Liss, Inc.