Unraveling profibrotic pathways in the kidney
Fibrosis is a hallmark of chronic kidney disease that is characterized by accumulation of extracellular matrix and an influx of immune cells. Autophosphorylation of serine residues within the type II TGF-β receptor (TβRII) following activation by TGF-β induces a SMAD-dependent profibrotic signaling cascade; however, there are multiple tyrosine residues within the cytoplasmic tail of TβRII that have potential to regulate this pathway. In this episode, Ambra Pozzi reveals that phosphorylation of tyrosine residues in the cytoplasmic tail of TβRII does influence the fibrotic signaling cascade. Specifically, Pozzi and colleagues determined that integrin α1β1 recruits the phosphatase TCPTP to TβRII, subsequently dephosphorylating tyrosine residues within the TβRII cytoplasmic tail. Furthermore, mice lacking α1β1 integrin exhibited enhanced phosphorylation of TβRII due to decreased recruitment of TCPTP, resulting in severe fibrosis following kidney injury.
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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
Copyright © 2024 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)