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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)3295-3310
Number of pages16
JournalJournal of Clinical Investigation
Volume124
Issue number8
DOIs
StatePublished - Aug 1 2014

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Non-Receptor Type 2 Protein Tyrosine Phosphatase
Integrins
Tyrosine
Tail
Fibrosis
Collecting Kidney Tubules
Collagen Receptors
Kidney
Ureteral Obstruction
Protein-Serine-Threonine Kinases
Serine
Chronic Kidney Failure
Phosphorylation
tyrosine receptor

ASJC Scopus subject areas

  • Medicine(all)

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Integrin-mediated type II TGF-β receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling. / Chen, Xiwu; Wang, Hongtao; Liao, Hong Jun; Hu, Wen; Gewin, Leslie; Mernaugh, Glenda; Zhang, Sheng; Zhang, Zhong-Yin; Vega-Montoto, Lorenzo; Vanacore, Roberto M.; Fässler, Reinhard; Zent, Roy; Pozzi, Ambra.

In: Journal of Clinical Investigation, Vol. 124, No. 8, 01.08.2014, p. 3295-3310.

Research output: Contribution to journalArticle

Chen, X, Wang, H, Liao, HJ, Hu, W, Gewin, L, Mernaugh, G, Zhang, S, Zhang, Z-Y, Vega-Montoto, L, Vanacore, RM, Fässler, R, Zent, R & Pozzi, A 2014, 'Integrin-mediated type II TGF-β receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling', Journal of Clinical Investigation, vol. 124, no. 8, pp. 3295-3310. https://doi.org/10.1172/JCI71668
Chen, Xiwu ; Wang, Hongtao ; Liao, Hong Jun ; Hu, Wen ; Gewin, Leslie ; Mernaugh, Glenda ; Zhang, Sheng ; Zhang, Zhong-Yin ; Vega-Montoto, Lorenzo ; Vanacore, Roberto M. ; Fässler, Reinhard ; Zent, Roy ; Pozzi, Ambra. / Integrin-mediated type II TGF-β receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 8. pp. 3295-3310.
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