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Transforming Growth Factor-β (TGF-β) Directly Activates the JAK1-STAT3 Axis to Induce Hepatic Fibrosis in

Liu-Ya Tang1, Mary Heller1, Zhaojing Meng2

  • 1From the Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.

The Journal of Biological Chemistry
|February 4, 2017
PubMed

Insights

Transforming growth factor-β (TGF-β) activates STATs through a SMAD-independent JAK1 pathway within minutes. A second SMAD-dependent phase requires protein synthesis, with JAK1/STAT3 and SMADs cooperating in liver fibrosis.

Area of Science:

  • Cellular biology
  • Molecular signaling
  • Hepatology

Background:

  • Transforming growth factor-β (TGF-β) mediates diverse biological effects via SMAD and non-SMAD pathways.
  • STATs and SMADs coordinate TGF-β functions in hepatic cells, but STAT activation mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the mechanism of STAT activation by TGF-β in hepatic cells.
  • To investigate the role of JAK1 and SMADs in TGF-β-induced STAT phosphorylation.
  • To determine the contribution of the JAK1/STAT pathway to TGF-β target gene expression and liver fibrosis.

Main Methods:

  • Investigated JAK1 as a TGFβRI binding protein.
  • Assessed STAT phosphorylation in a SMAD-independent manner following TGF-β stimulation.
  • Analyzed a second phase of STAT phosphorylation requiring SMADs and de novo protein synthesis.
  • Utilized global gene expression profiling in hepatic stellate cells.

Main Results:

  • JAK1 is constitutively bound to TGFβRI and essential for rapid, SMAD-independent STAT phosphorylation upon TGF-β stimulation.
  • A secondary phase of STAT phosphorylation occurs later, dependent on SMADs and de novo protein synthesis, with JAK1 involvement.
  • The non-SMAD JAK1/STAT pathway is crucial for a subset of TGF-β target genes in hepatic stellate cells.
  • Cooperation between JAK1-STAT3 and SMAD pathways is vital for TGF-β's role in liver fibrosis.

Conclusions:

  • JAK1 mediates an early, SMAD-independent STAT activation by TGF-β.
  • A later, SMAD-dependent STAT activation phase also involves JAK1 and protein synthesis.
  • The JAK1/STAT3 and SMAD pathways cooperate to drive TGF-β-induced liver fibrosis.
Keywords:
Janus kinase (JAK)Liver fibrosisSMAD transcription factorSTAT3Smad3hepatic stellate cell (HSC)transforming growth factor beta (TGF-B)

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