Gas6 Induces Mesangial Cell Proliferation via Latent Transcription Factor STAT3

Motoko Yanagita, Hidenori Arai, Toru Nakano, Kazumasa Ohashi, Kensaku Mizuno, Atsushi Fukatsu, Toshio Doi, Toru Kita

Research output: Contribution to journalArticlepeer-review

74 Citations (Scopus)

Abstract

Mesangial cell proliferation is essential for the pathogenesis and progression of glomerular disease. Previously, we showed that Gas6 plays a pivotal role in mesangial cell proliferation in vitro and in vivo. In the present study, we identified downstream targets of Gas6 signaling to examine the role in mesangial cell proliferation in vitro and in vivo. We found that Gas6 tyrosine phosphorylates STAT3 (signal transducers and activators of transcription) with concomitant translocation to the nucleus and induces STAT3-dependent transcriptional activation in cultured mesangial cells. Expressing dominant negative STAT3 inhibited Gas6-mediated transcriptional activation of STAT3 and abolished Gas6-induced mesangial cell proliferation. In a model of mesangial proliferative glomerulonephritis, STAT3 is phosphorylated in mesangial cells, and its phosphorylation peaks at day 8 after the injection of anti-Thy1.1 antibody. Inhibition of Gas6 by warfarin and the extracellular domain of its receptor, Axl, abolished phosphorylation of STAT3 in vivo. Thus, our in vitro and in vivo findings indicate that autocrine growth factor Gas6 induces mesangial cell proliferation via latent transcription factor STAT3. Therefore, STAT3 might be a new therapeutic target for kidney disease induced by mesangial proliferation.

Original languageEnglish
Pages (from-to)42364-42369
Number of pages6
JournalJournal of Biological Chemistry
Volume276
Issue number45
DOIs
Publication statusPublished - 2001 Nov 9

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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