Hematopoiesis Controlled by Distinct TIF1γ and Smad4 Branches of the TGFβ Pathway

Tissue homeostasis in mammals relies on powerful cytostatic and differentiation signals delivered by the cytokine TGFb and relayed within the cell via the activation of Smad transcription factors. Formation of transcription regulatory complexes by the association of Smad4 with receptor-phosphorylated Smads 2 and 3 is a central event in the canonical TGFb pathway. Here we provide evidence for a branching of this pathway. The ubiquitious nuclear protein Transcriptional Intermediary Factor 1g (TIF1g) selectively binds receptor-phosphorylated Smad2/3 in competition with Smad4. Rapid and robust binding of TIF1g to Smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to TGFb. In human hematopoietic stem/progenitor cells, where TGFb inhibits proliferation and stimulates erythroid differentiation, TIF1g mediates the differentiation response while Smad4 mediates the antiproliferative response with Smad2/3 participating in both responses. Thus, Smad2/3-TIF1g and Smad2/ 3-Smad4 function as complementary effector arms in the control of hematopoietic cell fate by the TGFb/Smad pathway.