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Integrin-mediated type II TGF-? receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling.

ABSTRACT: Tubulointerstitial fibrosis underlies all forms of end-stage kidney disease. TGF-? mediates both the development and the progression of kidney fibrosis through binding and activation of the serine/threonine kinase type II TGF-? receptor (T?RII), which in turn promotes a T?RI-mediated SMAD-dependent fibrotic signaling cascade. Autophosphorylation of serine residues within T?RII is considered the principal regulatory mechanism of T?RII-induced signaling; however, there are 5 tyrosine residues within the cytoplasmic tail that could potentially mediate T?RII-dependent SMAD activation. Here, we determined that phosphorylation of tyrosines within the T?RII tail was essential for SMAD-dependent fibrotic signaling within cells of the kidney collecting duct. Conversely, the T cell protein tyrosine phosphatase (TCPTP) dephosphorylated T?RII tail tyrosine residues, resulting in inhibition of T?R-dependent fibrotic signaling. The collagen-binding receptor integrin ?1?1 was required for recruitment of TCPTP to the T?RII tail, as mice lacking this integrin exhibited impaired TCPTP-mediated tyrosine dephosphorylation of T?RII that led to severe fibrosis in a unilateral ureteral obstruction model of renal fibrosis. Together, these findings uncover a crosstalk between integrin ?1?1 and T?RII that is essential for T?RII-mediated SMAD activation and fibrotic signaling pathways.

SUBMITTER: Chen X

PROVIDER: S-EPMC4109532 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Integrin-mediated type II TGF-β receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling.

Chen Xiwu X Wang Hongtao H Liao Hong-Jun HJ Hu Wen W Gewin Leslie L Mernaugh Glenda G Zhang Sheng S Zhang Zhong-Yin ZY Vega-Montoto Lorenzo L Vanacore Roberto M RM Fässler Reinhard R Zent Roy R Pozzi Ambra A

The Journal of clinical investigation 20140701 8

Tubulointerstitial fibrosis underlies all forms of end-stage kidney disease. TGF-β mediates both the development and the progression of kidney fibrosis through binding and activation of the serine/threonine kinase type II TGF-β receptor (TβRII), which in turn promotes a TβRI-mediated SMAD-dependent fibrotic signaling cascade. Autophosphorylation of serine residues within TβRII is considered the principal regulatory mechanism of TβRII-induced signaling; however, there are 5 tyrosine residues with ...[more]

PMID: 24983314

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Project description:AimPaeoniflorin has shown to attenuate bleomycin-induced pulmonary fibrosis (PF) in mice. Because the epithelial-mesenchymal transition (EMT) in type 2 lung endothelial cells contributes to excessive fibroblasts and myofibroblasts during multiple fibrosis of tissues, we investigated the effects of paeoniflorin on TGF-? mediated pulmonary EMT in bleomycin-induced PF mice.MethodsPF was induced in mice by intratracheal instillation of bleomycin (5 mg/kg). The mice were orally treated with paeoniflorin or prednisone for 21 d. After the mice were sacrificed, lung tissues were collected for analysis. An in vitro EMT model was established in alveolar epithelial cells (A549 cells) incubated with TGF-?1 (2 ng/mL). EMT identification and the expression of related proteins were performed using immunohistochemistry, transwell assay, ELISA, Western blot and RT-qPCR.ResultsIn PF mice, paeoniflorin (50, 100 mg·kg(-1)·d(-1)) or prednisone (6 mg·kg(-1)·d(-1)) significantly decreased the expression of FSP-1 and ?-SMA, and increased the expression of E-cadherin in lung tissues. In A549 cells, TGF-?1 stimulation induced EMT, as shown by the changes in cell morphology, the increased cell migration, and the increased vimentin and ?-SMA expression as well as type I and type III collagen levels, and by the decreased E-cadherin expression. In contrast, effects of paeoniflorin on EMT disappeared when the A549 cells were pretreated with TGF-?1 for 24 h. TGF-?1 stimulation markedly increased the expression of Snail and activated Smad2/3, Akt, ERK, JNK and p38 MAPK in A549 cells. Co-incubation with paeoniflorin (1-30 ?mol/L) dose-dependently attenuated TGF-?1-induced expression of Snail and activation of Smad2/3, but slightly affected TGF-?1-induced activation of Akt, ERK, JNK and p38 MAPK. Moreover, paeoniflorin markedly increased Smad7 level, and decreased ALK5 level in A549 cells.ConclusionPaeoniflorin suppresses the early stages of TGF-? mediated EMT in alveolar epithelial cells, likely by decreasing the expression of the transcription factors Snail via a Smad-dependent pathway involving the up-regulation of Smad7.

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Integrin-mediated type II TGF-? receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling.

Publications

Integrin-mediated type II TGF-β receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling.

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