Inhibitors of clathrin-dependent endocytosis enhance TGFbeta signaling and responses.

Abstract

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.

• Authors: Chun-Lin Chen, Wei-Hsien Hou, I-Hua Liu, George Hsiao, Shuan Shian Huang, Jung San Huang
• Journal: Journal of cell science (J Cell Sci) Vol. 122 Issue Pt 11 Pg. 1863-71 (Jun 01 2009) ISSN: 0021-9533 [Print] England
• PMID: 19461075 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Apolipoproteins E
• Carrier Proteins
• Clathrin
• Enzyme Inhibitors
• Hydrazones
• N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide
• Plasminogen Activator Inhibitor 1
• Receptors, Transforming Growth Factor beta
• SARA protein, mouse
• Smad2 Protein
• Smad2 protein, mouse
• Transforming Growth Factor beta
• beta-Cyclodextrins
• Monensin
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I
• GTP-Binding Proteins
• monodansylcadaverine
• betadex
• Cadaverine
• Triflupromazine

Topics

• Animals
• Apolipoproteins E (genetics, metabolism)
• Cadaverine (analogs & derivatives, pharmacology)
• Carrier Proteins (genetics, metabolism)
• Cell Line
• Clathrin (metabolism)
• Endocytosis (drug effects, physiology)
• Enzyme Inhibitors (pharmacology)
• Female
• GTP-Binding Proteins
• Hydrazones (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Monensin (pharmacology)
• Plasminogen Activator Inhibitor 1 (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta (genetics, metabolism)
• Signal Transduction (drug effects, physiology)
• Smad2 Protein (metabolism)
• Transforming Growth Factor beta (metabolism)
• Triflupromazine (pharmacology)
• beta-Cyclodextrins (pharmacology)