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

39 Scopus citations

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

ASJC Scopus subject areas

  • Medicine(all)

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    Chen, X., Wang, H., Liao, H. J., Hu, W., Gewin, L., Mernaugh, G., Zhang, S., Zhang, Z. Y., Vega-Montoto, L., Vanacore, R. M., 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, 124(8), 3295-3310. https://doi.org/10.1172/JCI71668