Here we describe human colon carcinoma cell clones, isolated from a transforming growth factor beta (TGF-beta)-responsive parental cell line, which display differential sensitivities to TGF-beta 1 and TGF-beta 2 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-beta 2 (IC50 = 0.1-0.2 ng/ml), but were resistant to TGF-beta 1 (IC50 > or = 5 ng/ml). In S1S2 cells, both TGF-beta isoforms resulted in a repression of c-myc mRNA expression, a concentration-dependent increase in fibronectin 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-beta 2 elicited these responses, yet TGF-beta 1 was essentially without effect. Receptor cross-linking experiments indicated that TGF-beta 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-beta 2 but not by TGF-beta 1. These data suggest that either the TGF-beta 1 and TGF-beta 2 isoforms differ with respect to their ability to interact with the type I and II classes of receptors, or the TGF-beta 1 and TGF-beta 2 isoforms can interact with distinct receptor proteins of the type I and II classes in this model system.