Molecular mechanisms of inactivation of TGF-β receptors during carcinogenesis

Abstract Signals from the TGF-βs are mediated by the TGF-β receptors and their substrates, the Smad proteins. Inactivation of either of the two transmembrane serine/threonine kinases called the TGF-β type I and type II receptors is now known to underlie a wide variety of human pathologies including, especially carcinogenesis. Numerous studies have now demonstrated that the TGF-β receptor complex and its downstream signaling intermediates constitute a tumor suppressor pathway. We review here a specific pathway of mutational inactivation of the TGF-β type II receptor resulting from microsatellite instability and demonstrate that, by contrast, the most common mechanism of loss of expression of the TGF-β type II receptor involves transcriptional repression. This provides a new target for therapeutic intervention.