A Dominant Inhibitory Mutant of the Type II Transforming Growth Factor β Receptor in the Malignant Progression of a Cutaneous T-Cell Lymphoma

Abstract

In many cancers, inactivating mutations in both alleles of the transforming growth factor β (TGF-β) type II receptor (TβRII) gene occur and correlate with loss of sensitivity to TGF-β. Here we describe a novel mechanism for loss of sensitivity to growth inhibition by TGF-β in tumor development. Mac-1 cells, isolated from the blood of a patient with an indolent form of cutaneous T-cell lymphoma, express wild-type TβRII and are sensitive to TGF-β. 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-β. They express both the wild-type TβRII and a receptor with a single point mutation (Asp-404→Gly [D404G]) in the kinase domain (D404G-TβRII); no TβRI or TβRII is found on the plasma membrane, suggesting that D404G-TβRII 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-TβRII in TGF-β-sensitive Mac-1 cells as well as in Hep3B hepatoma cells results in resistance to TGF-β and disappearance of cell surface TβRI and TβRII. Overexpression of wild-type TβRII in Mac-2A cells restores cell surface TβRI and TβRII and sensitivity to TGF-β. The ability of the D404G-TβRII to dominantly inhibit function of wild-type TGF-β receptors represents a new mechanism for loss of sensitivity to the growth-inhibitory functions of TGF-β in tumor development.