Integrin-mediated type II TGF-β receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling

J Clin Invest. 2014 Aug;124(8):3295-310. doi: 10.1172/JCI71668. Epub 2014 Jul 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Collagen / biosynthesis
  • Epithelial-Mesenchymal Transition
  • Fibrosis
  • Integrin alpha1 / genetics
  • Integrin alpha1 / metabolism
  • Integrin alpha1beta1 / metabolism*
  • Kidney / metabolism
  • Kidney / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / metabolism
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / chemistry
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction
  • Smad Proteins / metabolism*
  • Smad2 Protein / metabolism
  • Smad3 Protein / metabolism
  • Tyrosine / chemistry
  • Ureteral Obstruction / metabolism
  • Ureteral Obstruction / pathology

Substances

  • Integrin alpha1
  • Integrin alpha1beta1
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Tyrosine
  • Collagen
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2