Betulinic acid enhances TGF-β signaling by altering TGF-β receptors partitioning between lipid-raft/caveolae and non-caveolae membrane microdomains in mink lung epithelial cells

Background TGF-β is a key modulator in the regulation of cell proliferation and migration, and is also involved in the process of cancer development and progression. Previous studies have indicated that TGF-β responsiveness is determined by TGF-β receptor partitioning between lipid raft/caveolae-mediated and clathrin-mediated endocytosis. Lipid raft/caveolae-mediated endocytosis facilitates TGF-β degradation and thus suppressing TGF-β responsiveness. By contrast, clathrin-mediated endocytosis results in Smad2/3-dependent endosomal signaling, thereby promoting TGF-β responsiveness. Because betulinic acid shares a similar chemical structure with cholesterol and has been reported to insert into the plasma membrane, we speculate that betulinic acid changes the fluidity of the plasma membrane and modulates the signaling pathway associated with membrane microdomains. We propose that betulinic acid modulates TGF-β responsiveness by changing the partitioning of TGF-β receptor between lipid-raft/caveolae and non-caveolae microdomain on plasma membrane.