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

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.

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Chen, Xiwu1, Autor
Wang, Hongtao1, Autor
Liao, Hong-Jun1, Autor
Hu, Wen1, Autor
Gewin, Leslie1, Autor
Mernaugh, Glenda1, Autor
Zhang, Sheng1, Autor
Zhang, Zhong-Yin1, Autor
Vega-Montoto, Lorenzo1, Autor
Vanacore, Roberto M.1, Autor
Fässler, Reinhard2, Autor           
Zent, Roy1, Autor
Pozzi, Ambra1, Autor
Affiliations:
1external, ou_persistent22              
2Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565147              

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Schlagwörter: TUBULOINTERSTITIAL FIBROSIS; MESENCHYMAL TRANSITION; GLOMERULAR INJURY; PHOSPHATASE TCPTP; NEGATIVE REGULATION; COLLAGEN-SYNTHESIS; EPITHELIAL-CELLS; KIDNEY-DISEASE; URETERAL BUD; ALPHA-1-BETA-1
 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.

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Sprache(n): eng - English
 Datum: 2014-08
 Publikationsstatus: Erschienen
 Seiten: 16
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: ISI: 000339984000008
DOI: 10.1172/JCI71668
 Art des Abschluß: -

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Titel: JOURNAL OF CLINICAL INVESTIGATION
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA : AMER SOC CLINICAL INVESTIGATION INC
Seiten: - Band / Heft: 124 (8) Artikelnummer: - Start- / Endseite: 3295 - 3310 Identifikator: ISSN: 0021-9738