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Integrin-mediated type II TGF-β receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling
Xiwu Chen, … , Roy Zent, Ambra Pozzi
Xiwu Chen, … , Roy Zent, Ambra Pozzi
Published July 1, 2014
Citation Information: J Clin Invest. 2014;124(8):3295-3310. https://doi.org/10.1172/JCI71668.
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Research Article Nephrology Article has an altmetric score of 10

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

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Abstract

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 within the cytoplasmic tail that could potentially mediate TβRII-dependent SMAD activation. Here, we determined that phosphorylation of tyrosines within the TβRII tail was essential for SMAD-dependent fibrotic signaling within cells of the kidney collecting duct. Conversely, the T cell protein tyrosine phosphatase (TCPTP) dephosphorylated TβRII tail tyrosine residues, resulting in inhibition of TβR-dependent fibrotic signaling. The collagen-binding receptor integrin α1β1 was required for recruitment of TCPTP to the TβRII tail, as mice lacking this integrin exhibited impaired TCPTP-mediated tyrosine dephosphorylation of TβRII that led to severe fibrosis in a unilateral ureteral obstruction model of renal fibrosis. Together, these findings uncover a crosstalk between integrin α1β1 and TβRII that is essential for TβRII-mediated SMAD activation and fibrotic signaling pathways.

Authors

Xiwu Chen, Hongtao Wang, Hong-Jun Liao, Wen Hu, Leslie Gewin, Glenda Mernaugh, Sheng Zhang, Zhong-Yin Zhang, Lorenzo Vega-Montoto, Roberto M. Vanacore, Reinhard Fässler, Roy Zent, Ambra Pozzi

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Figure 6

TCPTP regulates TβRII tyrosine phosphorylation and signaling.

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TCPTP regulates TβRII tyrosine phosphorylation and signaling.
(A) Cell l...
(A) Cell lysates (0.5 mg) from serum-starved WT and α1KO CD cells were immunoprecipitated with the anti-phosphotyrosine antibody 4G10 (10 μg) or with mouse IgG isotype control antibody (10 μg) and analyzed by Western blot. A band corresponding to TβRII (~68 kDa) was visible only in α1KO cells incubated with 4G10. Tyrosine-phosphorylated products (50–100 kDa) were detected with anti-pY99 antibodies in both WT and α1KO CD cells. (B) Morphology of WT CD cells stably transfected with shRNAi control (ShC) or TCPTP shRNAi (Sh-TCPTP). (C and D) Cell lysates (20 μg/lane) from serum-starved WT CD cells transfected with ShC (1 clone shown) or Sh-TCPTP (3 clones shown) and treated with or without SB431542 (SB) were analyzed by Western blot for levels of TCPTP, pSMAD3, SMAD3, and collagen I. (E) WT CD cells were cultured on plastic in 0.2% serum with or without the TCPTP inhibitor compound 8 (TCPTP-I) for 4 days and then stained with anti–ZO-1 and anti-αSMA antibodies. (F) Serum-starved WT CD cells were treated with TCPTP inhibitor at the concentrations indicated. After 24 hours, cell lysates (20 μg/lane) were analyzed for levels of collagen IV, pSMAD3, and SMAD3. (G) Cell lysates (0.5 mg) from serum-starved WT CD cells transfected with control or TCPTP shRNAi (1 clone each shown) were immunoprecipitated and analyzed by Western blot as in A. A band corresponding to TβRII was more evident in lysates of CD cells transfected with TCPTP shRNAi. Scale bars: 20 μm (B and E).

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