Albumin endocytosis in endothelial cells induces TGF- receptor II signaling

Siddiqui, Shahid S., Zeba K. Siddiqui, and Asrar B. Malik. Albumin endocytosis in endothelial cells induces TGFreceptor II signaling. Am J Physiol Lung Cell Mol Physiol 286: L1016–L1026, 2004. First published January 16, 2004; 10.1152/ajplung.00356.2003.—Vascular endothelial cells undergo albumin endocytosis using a set of albumin binding proteins. This process is important for maintaining cellular homeostasis. We showed by several criteria that the previously described 73-kDa endothelial cell surface albumin binding protein is the 75-kDa transforming growth factor (TGF)receptor type II (T RII). Albumin coimmunoprecipitated with T RII from a membrane fraction from rat lung microvascular endothelial cells. Albumin endocytosis-negative COS-7 cells became albumin endocytosis competent when transfected with wild-type T RII but not when transfected with a domain-negative kinase mutant of T RII. An antibody specific for T RII inhibited albumin endocytosis. A mink lung epithelial cell line, which expresses both the TGFreceptor type I (T RI) and the T RII receptor, exhibited albumin binding to the cell surface and endocytosis. In contrast, mutant L-17 and DR-26 cells lacking T RI or T RII, respectively, each showed a dramatic reduction in binding and endocytosis. Albumin endocytosis induced Smad2 phosphorylation and Smad4 translocation as well as increased protein expression of the inhibitory Smad, Smad7. We identified regions of significant homology between amino acid sequences of albumin and TGF, suggesting a structural basis for the interaction of albumin with the TGFreceptors and subsequent activation of T RII signaling. The observed albumin-induced internalization of T RII signaling may be an important mechanism in the vessel wall for controlling TGFresponses in endothelial cells.