Transforming Growth Factor β Isoform-specific Differences in Interactions with Type I and II Transforming Growth Factor β Receptors

Here we describe human colon carcinoma cell clones, isolated from a transforming growth factor β (TGF-β)-responsive parental cell line, which display differential sensitivities to TGF β1 and TGF-β2 isoforms. In a monolayer proliferation assay, some clones were sensitive to both isoforms (IC50 = 0.1-0.6 ng/ml; S1S2) while others were resistant to both isoforms (IC50 < 5 ng/ml; R1R2). Still other clones (R1S2) were sensitive to TGF-02 (IC50 = 0.1-0.2 ng/ml), but were resistant to TGF-β1 (IC50 ≥ 5 ng/ml). In S1S2 cells, both TGF-β isoforms resulted in a repression of c-myc mRNA expression, a concentration-dependent increase in fibronec-tin levels, and an enhanced production of the colon cell differentiation marker carcinoembryonic antigen. In contrast, R1R2 cells did not display these responses, or did so only to a limited extent In R1S2 cells, TGF-β elicited these responses, yet TGF-β, was essentially without effect Receptor cross-linking experiments indicated that TGF-β resistance in this model system was not generally associated with a complete lack of expression of either type I or II receptors. Moreover, the R1S2 type clones were heterogeneous, although the majority of them displayed binding to type I receptors by TGF-β2 but not by TGF-β1,. These data suggest that either the TGF-β1 and TGF-β2 isoforms differ with respect to their ability to interact with the type I and II classes of receptors, or the TGF-β1 and TGF-β2 isoforms can interact with distinct receptor proteins of the type I and II classes in this model system.