Klotho inhibits transforming growth factor-β1 (TGF-β1) signaling and suppresses renal fibrosis and cancer metastasis in mice

Shigehiro Doi, Yonglong Zou, Osamu Togao, Johanne V. Pastor, George B. John, Lei Wang, Kazuhiro Shiizaki, Russell Gotschall, Susan Schiavi, Noriaki Yorioka, Masaya Takahashi, David A. Boothman, Makoto Kuro-o

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328 Citations (Scopus)

Abstract

Fibrosis is a pathological process characterized by infiltration and proliferation of mesenchymal cells in interstitial space. A substantial portion of these cells is derived from residing non-epithelial and/or epithelial cells that have acquired the ability to migrate and proliferate. The mesenchymal transition is also observed in cancer cells to confer the ability to metastasize. Here, we show that renal fibrosis induced by unilateral ureteral obstruction and metastasis of human cancer xenografts are suppressed by administration of secreted Klotho protein to mice. Klotho is a single-pass transmembrane protein expressed in renal tubular epithelial cells. The extracellular domain of Klotho is secreted by ectodomain shedding. Secreted Klotho protein directly binds to the type-II TGF-β receptor and inhibits TGF-β1 binding to cell surface receptors, thereby inhibiting TGF-β1 signaling. Klotho suppresses TGF-β1-induced epithelial-to-mesenchymal transition (EMT) responses in cultured cells, including decreased epithelial marker expression, increased mesenchymal marker expression, and/or increased cell migration. In addition to TGF-β1 signaling, secreted Klotho has been shown to inhibit Wnt and IGF-1 signaling that can promote EMT. These results have raised the possibility that secreted Klotho may function as an endogenous anti-EMT factor by inhibiting multiple growth factor signaling pathways simultaneously.

Original languageEnglish
Pages (from-to)8655-8665
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number10
DOIs
Publication statusPublished - Mar 11 2011

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Doi, S., Zou, Y., Togao, O., Pastor, J. V., John, G. B., Wang, L., Shiizaki, K., Gotschall, R., Schiavi, S., Yorioka, N., Takahashi, M., Boothman, D. A., & Kuro-o, M. (2011). Klotho inhibits transforming growth factor-β1 (TGF-β1) signaling and suppresses renal fibrosis and cancer metastasis in mice. Journal of Biological Chemistry, 286(10), 8655-8665. https://doi.org/10.1074/jbc.M110.174037