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

Tubulointerstitial fibrosis underlies all forms of end-stage kidney disease. TGF-ß mediates both the development and the progression of kidney fibrosis through binding and activation of the serine/threonine kinase type II TGF-ß receptor (TßRII), which in turn promotes a TßRI-mediated SMAD-dependent fibrotic signaling cascade. Autophosphorylation of serine residues within TßRII is considered the principal regulatory mechanism of TßRII-induced signaling; however, there are 5 tyrosine residues within the cytoplasmic tail that could potentially mediate TßRII-dependent SMAD activation. Here, we determined that phosphorylation of tyrosines within the TßRII tail was essential for SMAD-dependent fibrotic signaling within cells of the kidney collecting duct. Conversely, the T cell protein tyrosine phosphatase (TCPTP) dephosphorylated TßRII tail tyrosine residues, resulting in inhibition of TßR-dependent fibrotic signaling. The collagen-binding receptor integrin α1ß1 was required for recruitment of TCPTP to the TßRII tail, as mice lacking this integrin exhibited impaired TCPTP-mediated tyrosine dephosphorylation of TßRII that led to severe fibrosis in a unilateral ureteral obstruction model of renal fibrosis. Together, these findings uncover a crosstalk between integrin α1ß1 and TßRII that is essential for TßRII-mediated SMAD activation and fibrotic signaling pathways.