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p38 MAPK mediates fibrogenic signal through smad3 phosphorylation in rat myofibroblasts
Author(s) -
Furukawa Fukiko,
Matsuzaki Koichi,
Mori Shigeo,
Tahashi Yoshiya,
Yoshida Katsunori,
Sugano Yasushi,
Yamagata Hideo,
Matsushita Masanori,
Seki Toshihito,
Inagaki Yutaka,
Nishizawa Mikio,
Fujisawa Junichi,
Inoue Kyoichi
Publication year - 2003
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.1840380414
Subject(s) - phosphorylation , transdifferentiation , microbiology and biotechnology , phosphorylation cascade , mapk/erk pathway , p38 mitogen activated protein kinases , kinase , signal transduction , biology , hepatic stellate cell , chemistry , protein kinase a , protein phosphorylation , endocrinology , stem cell
Hepatic stellate cells (HSCs) spontaneously transdifferentiate into myofibroblast (MFB)‐phenotype on plastic dishes. This response recapitulates the features of activation in vivo. Transforming growth factor β (TGF‐β) plays a prominent role in stimulating liver fibrogenesis by MFBs. In quiescent HSCs, TGF‐β signaling involves TGF‐β type I receptor (TβRI)‐mediated phosphorylation of serine residues within the conserved SSXS motif at the C‐terminus of Smad2 and Smad3. The middle linker regions of Smad2 and Smad3 also are phosphorylated by mitogenactivated protein kinase (MAPK). This study elucidates the change of Smad3‐mediated signals during the transdifferentiation process. By using antibodies highly specific to the phosphorylated C‐terminal region and the phosphorylated linker region of Smad3, we found that TGF‐β‐dependent Smad3 phosphorylation at the C‐terminal region decreased, but that the phosphorylation at the linker region increased in the process of transdifferentiation. TGF‐β activated the p38 MAPK pathway, further leading to Smad3 phosphorylation at the linker region in the cultured MFBs, irrespective of Smad2. The phosphorylation promoted hetero‐complex formation and nuclear translocation of Smad3 and Smad4. Once combined with TβRI‐phosphorylated Smad2, the Smad3 and Smad4 complex bound to plasminogen activator inhibitor‐type I promoter could enhance the transcription. In addition, Smad3 phosphorylation mediated by the activated TβRI was impaired severely in MFBs during chronic liver injury, whereas Smad3 phosphorylation at the linker region was remarkably induced by p38 MAPK pathway. In conclusion, p38 MAPK—dependent Smad3 phosphorylation promoted extracellular matrix production in MFBs both in vitro and in vivo. (Hepatology 2003;38:879–889).