TY - JOUR
T1 - Tumor necrosis factor-α regulates transforming growth factor-β-dependent epithelial-mesenchymal transition by promoting hyaluronan-CD44-moesin interaction
AU - Takahashi, Eri
AU - Nagano, Osamu
AU - Ishimoto, Takatsugu
AU - Yae, Toshifumi
AU - Suzuki, Yoshimi
AU - Shinoda, Takeshi
AU - Nakamura, Satoshi
AU - Niwa, Shinichiro
AU - Ikeda, Shun
AU - Koga, Hisashi
AU - Tanihara, Hidenobu
AU - Saya, Hideyuki
PY - 2010/2/5
Y1 - 2010/2/5
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M109.056523
DO - 10.1074/jbc.M109.056523
M3 - Article
C2 - 19965872
AN - SCOPUS:77950501023
SN - 0021-9258
VL - 285
SP - 4060
EP - 4073
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 6
ER -