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Integrin-mediated type II TGF-beta receptor tyrosine dephosphorylation controls SWIAD-dependent profibrotic signaling

MPG-Autoren
http://pubman.mpdl.mpg.de/cone/persons/resource/persons77945

Fässler,  Reinhard
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Zitation

Chen, X., Wang, H., Liao, H.-J., Hu, W., Gewin, L., Mernaugh, G., et al. (2014). Integrin-mediated type II TGF-beta receptor tyrosine dephosphorylation controls SWIAD-dependent profibrotic signaling. JOURNAL OF CLINICAL INVESTIGATION, 124(8), 3295-3310. doi:10.1172/JCI71668.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0023-D9FF-C
Zusammenfassung
Tubulointerstitial fibrosis underlies all forms of end-stage kidney disease. TGF-beta mediates both the development and the progression of kidney fibrosis through binding and activation of the serine/threonine kinase type II TGF-beta receptor (T beta RII), which in turn promotes a T beta RI-mediated SMAD-dependent fibrotic signaling cascade. Autophosphorylation of serine residues within T beta RII is considered the principal regulatory mechanism of T beta RII-induced signaling; however, there are 5 tyrosine residues within the cytoplasmic tail that could potentially mediate T beta RII-dependent SMAD activation. Here, we determined that phosphorylation of tyrosines within the T beta 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 beta RII tail tyrosine residues, resulting in inhibition of T beta R-dependent fibrotic signaling. The collagen-binding receptor integrin OM was required for recruitment of TCPTP to the T beta RII tail, as mice lacking this integrin exhibited impaired TCPTP-mediated tyrosine dephosphorylation of T beta RII that led to severe fibrosis in a unilateral ureteral obstruction model of renal fibrosis. Together, these findings uncover a crosstalk between integrin alpha 1 beta 1 and T beta RII that is essential for T beta RII-mediated SMAD activation and fibrotic signaling pathways.