摘要Members of the transforming growth factor-β(TGF-β)family control a broad range of cellular responses in metazoan organisms via autocrine,paracrine,and endocrine modes.Thus,aberrant TGF-β signaling can play a key role in the pathogenesis of several diseases.including cancer.TGF-βsignaling pathways are activated by a short phospho-cascade,from receptor phosphorylation to the subsequent phosphorylation and activation of downstream signal transducers called R-Smads.R-Smad phosphorylation state determines Smad complex assembly/disassembly,nuclear import/export,transcriptional activity and stability,and iS thus the most critical event in TGF-β signaling.Dephosphorylation of R-Smads by specific phosphatases prevents or terminates TGF-β signaling,highlighting the need to consider Smad(de)phosphorylation as a tightly controlled and dynamic event.This article illustrates the es-sential roles of reversible phosphorylation in controlling the strength and duration of TGF-β signaling and the eusu-ing physiological responses.