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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:AimsAngiotensin (Ang) II signalling has been suggested to promote cardiac fibrosis in inflammatory heart diseases; however, the underlying mechanisms remain obscure. Using Agtr1a-/- mice with genetic deletion of angiotensin receptor type 1 (ATR1) and the experimental autoimmune myocarditis (EAM) model, we aimed to elucidate the role of Ang II-ATR1 pathway in development of heart-specific autoimmunity and post-inflammatory fibrosis.Methods and resultsEAM was induced in wild-type (WT) and Agtr1a-/- mice by subcutaneous injections with alpha myosin heavy chain peptide emulsified in complete Freund's adjuvant. Agtr1a-/- mice developed myocarditis to a similar extent as WT controls at day 21 but showed reduced fibrosis and better systolic function at day 40. Crisscross bone marrow chimaera experiments proved that ATR1 signalling in the bone marrow compartment was critical for cardiac fibrosis. Heart infiltrating, bone-marrow-derived cells produced Ang II, but lack of ATR1 in these cells reduced transforming growth factor beta (TGF-β)-mediated fibrotic responses. At the molecular level, Agtr1a-/- heart-inflammatory cells showed impaired TGF-β-mediated phosphorylation of Smad2 and TAK1. In WT cells, TGF-β induced formation of RhoA-GTP and RhoA-A-kinase anchoring protein-Lbc (AKAP-Lbc) complex. In Agtr1a-/- cells, stabilization of RhoA-GTP and interaction of RhoA with AKAP-Lbc were largely impaired. Furthermore, in contrast to WT cells, Agtr1a-/- cells stimulated with TGF-β failed to activate canonical Wnt pathway indicated by suppressed activity of glycogen synthase kinase-3 (GSK-3)β and nuclear β-catenin translocation and showed reduced expression of Wnts. In line with these in vitro findings, β-catenin was detected in inflammatory regions of hearts of WT, but not Agtr1a-/- mice and expression of canonical Wnt1 and Wnt10b were lower in Agtr1a-/- hearts.ConclusionAng II-ATR1 signalling is critical for development of post-inflammatory fibrotic remodelling and dilated cardiomyopathy. Our data underpin the importance of Ang II-ATR1 in effective TGF-β downstream signalling response including activation of profibrotic Wnt/β-catenin pathway.

Dataset Information

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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