Open AccessInhibitors of clathrin-dependent endocytosis enhance TGFβ signaling and responses
Author(s) -
Chunlin Chen,
Wen Hsuan Hou,
IHua Liu,
George Hsiao,
Shuan Shian Huang,
Jung San Huang
Publication year - 2009
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.038729
Subject(s) - endocytosis , biology , internalization , microbiology and biotechnology , dynamin , clathrin , signal transduction , phosphorylation , smad2 protein , receptor mediated endocytosis , caveolae , transforming growth factor beta , cell , biochemistry
Clathrin-dependent endocytosis is believed to be involved in TGFbeta-stimulated cellular responses, but the subcellular locus at which TGFbeta induces signaling remains unclear. Here, we demonstrate that inhibitors of clathrin-dependent endocytosis, which are known to arrest the progression of endocytosis at coated-pit stages, inhibit internalization of cell-surface-bound TGFbeta and promote colocalization and accumulation of TbetaR-I and SARA at the plasma membrane. These inhibitors enhance TGFbeta-induced signaling and cellular responses (Smad2 phosphorylation/nuclear localization and expression of PAI-1). Dynasore, a newly identified inhibitor of dynamin GTPase activity, is one of the most potent inhibitors among those tested and, furthermore, is a potent enhancer of TGFbeta. Dynasore ameliorates atherosclerosis in the aortic endothelium of hypercholesterolemic ApoE-null mice by counteracting the suppressed TGFbeta responsiveness caused by the hypercholesterolemia, presumably acting through its effect on TGFbeta endocytosis and signaling in vascular cells.