Inhibitors of clathrin-dependent endocytosis enhance TGFbeta signaling and responses.
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.
Chen
Chun-Lin
CL
Department of Biochemistry, Saint Louis University School of Medicine, Doisy Research Center, St Louis, MO 63104, USA.
Hou
Wei-Hsien
WH
Liu
I-Hua
IH
Hsiao
George
G
Huang
Shuan Shian
SS
Huang
Jung San
JS
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D002103:Cadaverine / Q000031:analogs & derivatives / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002966:Clathrin / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins; D006835:Hydrazones / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008985:Monensin / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014273:Triflupromazine / Q000494:pharmacology; D047392:beta-Cyclodextrins / Q000494:pharmacology
D001057:Apolipoproteins E; D002352:Carrier Proteins; D002966:Clathrin; D004791:Enzyme Inhibitors; D006835:Hydrazones; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D017395:Plasminogen Activator Inhibitor 1; D018125:Receptors, Transforming Growth Factor beta; C491124:SARA protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta; D047392:beta-Cyclodextrins; D008985:Monensin; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D019204:GTP-Binding Proteins; C008542:monodansylcadaverine; C031215:betadex; D002103:Cadaverine; D014273:Triflupromazine