Inhibitory Smads: Mechanisms of Action and Roles in Human Diseases

Abstract

Inhibitory Smads are one of the major inhibitory regulators of intracellular signaling mediated by TGF-β superfamily proteins. Inhibitory Smads repress TGF-β superfamily signaling by several different mechanisms at the levels of cellular membrane, cytoplasm, and nucleus. Importantly, expression of I-Smads is induced by TGF-β superfamily proteins themselves and other signaling pathways, indicating a key role for I-Smads in negative feedback or cross-talk control of TGF-β superfamily signaling. Probably, I-Smads tightly control intensity and duration of TGF-β superfamily signaling and maintain homeostasis. Indeed, there is accumulating evidence that aberrant I-Smads expression and activity contributes to human diseases induced by TGF-β superfamily proteins. Better understanding of the mechanisms underlying I-Smads regulation may thus provide novel therapeutic targets for diseases associated with TGF-β superfamily proteins