Scientific Publications by FDA Staff

J Biol Chem 2017 Mar 10;292(10):4302-12

TGF-beta directly activates the JAK1-STAT3 axis to induce hepatic fibrosis in coordination with SMAD pathway.

Tang LY, Heller M, Meng Z, Yu LR, Tang Y, Zhou M, Zhang YE

Transforming growth factor-beta (TGF-beta) signals through both SMAD and non-SMAD pathways to elicit a wide array of biological effects. Existing data have shown the association and coordination between STATs and SMADs in mediating TGF-beta functions in hepatic cells, but it is not clear how STATs are activated under these circumstances. Here, we report that JAK1 is a constitutive TGFbetaRI binding protein and is absolutely required for phosphorylation of STATs in a SMADs-independent manner within minutes of TGF-beta stimulation. Following the activation of SMADs, TGF-beta also induces a second phase of STAT phosphorylation that requires SMADs, de novo protein synthesis, and contribution from JAK1. Our global gene expression profiling indicate that the non-SMAD JAK1/STATs pathway is essential for the expression of a subset of TGF-beta target genes in hepatic stellate cells, and the cooperation between JAK1-STAT3 and SMADs pathways is critical to the roles of TGF-beta in liver fibrosis.