Swapping Smad Partners

Abstract

Members of the transforming growth factor β (TGF-β) family regulate essential processes like cell proliferation, cell death, and developmental morphogenesis. The Smad proteins carry signals from activated TGF-β receptors to the nucleus where they promote transcription of target genes. This process requires a series of protein-protein interactions that, as the details emerge, appear like a highly orchestrated dance in which the regulated Smad (R-Smads) spin deftly from partner to partner on their way from the cell membrane to the nucleus. Just how the R-Smad recognizes the appropriate partners at the correct time is clarified by the work of Qin et al. In the course of activation, Smad3 interacts with the TGF-β receptor, SARA (Smad anchor for receptor activation), and the common mediator Smad (Co-Smad) Smad4. All of these interactions occur through a single domain of Smad3 (the effector or MH2 domain). Qin et al. analyzed crystal structures of monomeric and trimeric Smad3 and of a complex of the MH2 domain of Smad3 with the Smad-binding domain of SARA. The structures revealed that monomeric Smad3, which is brought to the receptor by interaction with SARA, undergoes a conformational change when phosphorylated by the receptor to form activated Smad3 trimers. This structural change disrupted interaction with SARA but enhanced interaction of Smad3 (again through the MH2 domain) with another partner, the proto-oncogene product Ski, which functions to repress transcriptional activation by Smad3. It thus appears that in the absence of receptor activation, SARA acts to suppress Smad3 activation by favoring the monomeric state of Smad3. The activating phosphorylation by the receptor then promotes formation of Smad3 trimers, which interact in the nucleus with the negative feedback component Ski and probably with other coactivators, corepressors, and regulatory molecules. Moustakas and Heldin discuss these results. B. Y. Qin, S. S. Lam, J. J. Correia, K. Lin, Smad3 allostery links TGF-β receptor kinase activation to transcriptional control. Genes Dev. 16 , 1950-1963 (2002). [Abstract] [Full Text] A. Moustakas, C-H. Heldin, From mono- to oligo-Smads: The heart of the matter in TGF-β signal transduction, Genes Dev. 16 , 1867-1871 (2002). [Full Text]