New Branch to TGF-β Pathway

Abstract

Cytokines of the transforming growth factor-β (TGF-β) family have important roles in development, cancer, and other cellular processes. Abundant evidence shows that stimulated TGF-β receptors phosphorylate Smad2 and Smad3 proteins, which act in complexes with Smad4 to regulate transcription in the nucleus. New results from He et al. point to a distinct mechanism by which TGF-β can control gene regulation. The authors searched for binding partners for Smads 2 and 3 and identified the protein transcriptional intermediary factor 1γ (TIF1γ, also called TRIM33, RFG7, PTC7, or ectodermin), a protein that functions as a cofactor with nuclear receptors and other transcription factors and as a component of the histone deacetylase N-CoR1/HDAC3 complex. Exposure of human hematopoietic progenitor cells to TGF increased the usual association of Smads 2 and 3 with Smad4 but also increased formation of complexes of Smad2/3 with TIF1γ in an apparently competitive manner. In human hematopoietic stem cells, TGF-β promotes differentiation, and this effect required TIF1γ. Reduced abundance of TIF1γ after infection of cells with retroviruses encoding shRNA inhibited differentiation of the cells in culture. Depletion of Smad4 had no effect on differentiation. In other culture conditions in which stem cell proliferation is enhanced, TGF-β inhibits proliferation. This effect required the presence of Smads 2 and 3 but was not affected by depletion of TIF1γ. The authors therefore conclude that activated Smads 2 and 3 can trigger two separate transcriptional responses with distinct biological outcomes, depending on whether they act in association with Smad4 or TIF1γ.

W. He, D. C. Dorn, H. Erdjument-Bromage, P. Tempst, M. A. S. Moore, J. Massagué, Hematopoiesis controlled by distinct TIF1γ and Smad4 branches of the TGFβ pathway. Cell 125, 929-941 (2006). [PubMed]