Dominant inhibitory mutant of the type II transforming growth factor beta receptor in the malignant progression of a cutaneous T-cell lymphoma

In many cancers, inactivating mutations in both alleles of the transforming growth factor beta (TGF-beta) type II receptor (T beta RII) gene occur and correlate with loss of sensitivity to TGF-beta, Here we describe a novel mechanism for loss of sensitivity to growth inhibition by TGF-beta in tumor development. Mac-1 cells, isolated from the blood of a patient with an indolent form of cutaneou T-cell lymphoma, express wild-type T beta RII and are sensitive to TGF-beta, Mac-2A cells, clonally related to Mac-1 and isolated from a skin nodule of the same patient at a later, clinically aggressive stage of lymphoma, are resistant to TGF-beta. They express both the wild-type T beta RII and a receptor with a single point mutation (Asp-404-->Gly [D404G]) in the kinase domain (D404G-T beta RII); no T beta RI or T beta RII is found on the plasma membrane, suggesting that D404G-T beta RII dominantly inhibits the function of the wild-type receptor by inhibiting its appearance on the plasma membrane, Indeed, inducible expression, under control of a tetracycline-regulated promoter, of D404G-T beta RII in TGF-beta-sensitive Mac-1 cells as well as in Hep3B hepatoma cells results in resistance to TGF-beta and disappearance of cell surface T beta RI and T beta RII. Overexpression of wild-type T beta RTI in Mac-2A cells restores cell surface T beta RI and T beta RII and sensitivity to TGF-beta. The ability of the D404G-T beta RII to dominantly inhibit function of wild-type TGF-beta receptors represents a new mechanism for loss of sensitivity to the growth-inhibitory functions of TGF-beta in tumor development.