期刊
JOURNAL OF CELL SCIENCE
卷 122, 期 11, 页码 1863-1871出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.038729
关键词
Endocytosis inhibitor; TGF beta; Coated pit; Signaling; Enhancer; Atherosclerosis
类别
资金
- NIH [HL087463, AR052578]
Clathrin-dependent endocytosis is believed to be involved in TGF beta-stimulated cellular responses, but the subcellular locus at which TGF beta 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 TGF beta and promote colocalization and accumulation of T beta R-I and SARA at the plasma membrane. These inhibitors enhance TGF beta-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 TGF beta. Dynasore ameliorates atherosclerosis in the aortic endothelium of hypercholesterolemic ApoE-null mice by counteracting the suppressed TGF beta responsiveness caused by the hypercholesterolemia, presumably acting through its effect on TGF beta endocytosis and signaling in vascular cells.
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