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Transforming Growth Factor ß Isoform-specific Differences in Interactions with Type I and II Transforming Growth Factor ß Receptors¹

Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033 [G. L. S., K. M. M.], and Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, Ohio 43699 [G-H. K. Z., S. P., M. G. B.]

Here we describe human colon carcinoma cell clones, isolated from a transforming growth factor ß (TGF-ß)-responsive parental cell line, which display differential sensitivities to TGF-ß₁ and TGF-ß₂ 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-ß₂ (IC₅₀ = 0.1–0.2 ng/ml), but were resistant to TGF-ß₁ (IC₅₀ 5 ng/ml). In S₁S₂ cells, both TGF-ß 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-ß₂ elicited these responses, yet TGF-ß₁ was essentially without effect. Receptor cross-linking experiments indicated that TGF-ß 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-ß₂ but not by TGF-ß₁. These data suggest that either the TGF-ß₁ and TGF-ß₂ isoforms differ with respect to their ability to interact with the type I and II classes of receptors, or the TGF-ß₁ and TGF-ß₂ isoforms can interact with distinct receptor proteins of the type I and II classes in this model system.

¹ This work was supported by NIH Grants CA51452 and CA54816 to K. M. M. and CA50457 and CA38173 to M. G. B.

² To whom requests for reprints should be addressed, at Department of Pharmacology, Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA 17033.

³ Recipient of National Cancer Institute Research Career Development Award K04 CA59552.

Received 11/11/94. Accepted 3/15/95.