title: Integrin-mediated type II TGF-β receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling.
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.forename: Xiwu
authors.initials: X
authors.lastname: Chen
authors.forename: Hongtao
authors.initials: H
authors.lastname: Wang
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Liao
authors.forename: Wen
authors.initials: W
authors.lastname: Hu
authors.forename: Leslie
authors.initials: L
authors.lastname: Gewin
authors.forename: Glenda
authors.initials: G
authors.lastname: Mernaugh
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Vega-Montoto
authors.forename: Roberto M
authors.initials: RM
authors.lastname: Vanacore
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
mesh_terms: D000818:Animals; D003094:Collagen / Q000096:biosynthesis; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D039423:Integrin alpha1 / Q000235:genetics / Q000378:metabolism; D039222:Integrin alpha1beta1 / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology
chemical_list: D039423:Integrin alpha1; D039222:Integrin alpha1beta1; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D014443:Tyrosine; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2