| First Author | Chen X | Year | 2014 |
| Journal | J Clin Invest | Volume | 124 |
| Issue | 8 | Pages | 3295-310 |
| PubMed ID | 24983314 | Mgi Jnum | J:213777 |
| Mgi Id | MGI:5586589 | Doi | 10.1172/JCI71668 |
| Citation | Chen X, et al. (2014) Integrin-mediated type II TGF-beta receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling. J Clin Invest 124(8):3295-310 |
| abstractText | 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 (TbetaRII), which in turn promotes a TbetaRI-mediated SMAD-dependent fibrotic signaling cascade. Autophosphorylation of serine residues within TbetaRII is considered the principal regulatory mechanism of TbetaRII-induced signaling; however, there are 5 tyrosine residues within the cytoplasmic tail that could potentially mediate TbetaRII-dependent SMAD activation. Here, we determined that phosphorylation of tyrosines within the TbetaRII tail was essential for SMAD-dependent fibrotic signaling within cells of the kidney collecting duct. Conversely, the T cell protein tyrosine phosphatase (TCPTP) dephosphorylated TbetaRII tail tyrosine residues, resulting in inhibition of TbetaR-dependent fibrotic signaling. The collagen-binding receptor integrin alpha1beta1 was required for recruitment of TCPTP to the TbetaRII tail, as mice lacking this integrin exhibited impaired TCPTP-mediated tyrosine dephosphorylation of TbetaRII that led to severe fibrosis in a unilateral ureteral obstruction model of renal fibrosis. Together, these findings uncover a crosstalk between integrin alpha1beta1 and TbetaRII that is essential for TbetaRII-mediated SMAD activation and fibrotic signaling pathways. |
