Transforming Growth Factor-β (TGF-β) Directly Activates the JAK1-STAT3 Axis to Induce Hepatic Fibrosis in Coordination with the SMAD Pathway.
Transforming growth factor-β (TGF-β) 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-β functions in hepatic cells, but it is not clear how STATs are activated under these circumstances. Here, we report that JAK1 is a constitutive TGFβRI binding protein and is absolutely required for phosphorylation of STATs in a SMAD-independent manner within minutes of TGF-β stimulation. Following the activation of SMADs, TGF-β also induces a second phase of STAT phosphorylation that requires SMADs,de novoprotein synthesis, and contribution from JAK1. Our global gene expression profiling indicates that the non-SMAD JAK1/STAT pathway is essential for the expression of a subset of TGF-β target genes in hepatic stellate cells, and the cooperation between the JAK1-STAT3 and SMAD pathways is critical to the roles of TGF-β in liver fibrosis.
From the Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
Liu-Ya
LY
Tang
From the Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
Mary
M
Heller
the Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland 21702.
Zhaojing
Z
Meng
the Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland 21702.
Li-Rong
LR
Yu
From the Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
Yi
Y
Tang
the Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland 21702.
Ming
M
Zhou
From the Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and zhangyin@mail.nih.gov.
Ying E
0000-0003-2753-7601
YE
Zhang
D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D050796:STAT3 Transcription Factor; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1
Janus kinase (JAK); Liver fibrosis; SMAD transcription factor; STAT3; Smad3; hepatic stellate cell (HSC); transforming growth factor beta (TGF-B)