Tumor necrosis factor-α regulates transforming growth factor-β-dependent epithelial-mesenchymal transition by promoting hyaluronan-CD44-moesin interaction

Eri Takahashi, Osamu Nagano, Takatsugu Ishimoto, Toshifumi Yae, Yoshimi Suzuki, Takeshi Shinoda, Satoshi Nakamura, Shinichiro Niwa, Shun Ikeda, Hisashi Koga, Hidenobu Tanihara, Hideyuki Saya

Research output: Contribution to journalArticle

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Abstract

Aberrant epithelial-mesenchymal transition (EMT) is involved in development of fibrotic disorders and cancer invasion. Alterations of cell-extracellular matrix interaction also contribute to those pathological conditions. However, the functional interplay between EMT and cell-extracellular matrix interactions remains poorly understood.Wenow show that the inflammatory mediator tumor necrosis factor-α (TNF-α) induces the formation of fibrotic foci by cultured retinal pigment epithelial cells through activation of transforming growth factor-β (TGF-β) signaling in a manner dependent on hyaluronan-CD44-moesin interaction. TNF-α promoted CD44 expression and moesin phosphorylation by protein kinase C, leading to the pericellular interaction of hyaluronan and CD44. Formation of the hyaluronan-CD44-moesin complex resulted in both cell-cell dissociation and increased cellular motility through actin remodeling. Furthermore, this complex was found to be associated with TGF-β receptor II and clathrin at actin microdomains, leading to activation of TGF-β signaling. We established an in vivo model of TNF-α-induced fibrosis in the mouse eye, and such ocular fibrosis was attenuated in CD44-null mice. The production of hyaluronan and its interaction with CD44, thus, play an essential role in TNF-α-induced EMT and are potential therapeutic targets in fibrotic disorders.

Original languageEnglish
Pages (from-to)4060-4073
Number of pages14
JournalJournal of Biological Chemistry
Volume285
Issue number6
DOIs
Publication statusPublished - 2010 Feb 5

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Epithelial-Mesenchymal Transition
Transforming Growth Factors
Hyaluronic Acid
Tumor Necrosis Factor-alpha
Extracellular Matrix
Actins
Fibrosis
Chemical activation
Clathrin
Phosphorylation
Retinal Pigments
Growth Factor Receptors
Protein Kinase C
Epithelial Cells
moesin
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Tumor necrosis factor-α regulates transforming growth factor-β-dependent epithelial-mesenchymal transition by promoting hyaluronan-CD44-moesin interaction. / Takahashi, Eri; Nagano, Osamu; Ishimoto, Takatsugu; Yae, Toshifumi; Suzuki, Yoshimi; Shinoda, Takeshi; Nakamura, Satoshi; Niwa, Shinichiro; Ikeda, Shun; Koga, Hisashi; Tanihara, Hidenobu; Saya, Hideyuki.

In: Journal of Biological Chemistry, Vol. 285, No. 6, 05.02.2010, p. 4060-4073.

Research output: Contribution to journalArticle

Takahashi, Eri ; Nagano, Osamu ; Ishimoto, Takatsugu ; Yae, Toshifumi ; Suzuki, Yoshimi ; Shinoda, Takeshi ; Nakamura, Satoshi ; Niwa, Shinichiro ; Ikeda, Shun ; Koga, Hisashi ; Tanihara, Hidenobu ; Saya, Hideyuki. / Tumor necrosis factor-α regulates transforming growth factor-β-dependent epithelial-mesenchymal transition by promoting hyaluronan-CD44-moesin interaction. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 6. pp. 4060-4073.
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