¹Michael E. DeBakey Department of Surgery, Department of Molecular & Cellular Biology and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA

Correspondence: Xin-Hua Feng, Tel: (713)798-4756; Fax: (713)798-4093 E-mail: xfeng@bcm.edu

Abstract

Members of the transforming growth factor- (TGF-) family control a broad range of cellular responses in metazoan organisms via autocrine, paracrine, and endocrine modes. Thus, aberrant TGF- signaling can play a key role in the pathogenesis of several diseases, including cancer. TGF- signaling 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- signaling. Dephosphorylation of R-Smads by specific phosphatases prevents or terminates TGF- signaling, highlighting the need to consider Smad (de)phosphorylation as a tightly controlled and dynamic event. This article illustrates the essential roles of reversible phosphorylation in controlling the strength and duration of TGF- signaling and the ensuing physiological responses.