Inhibitors of clathrin-dependent endocytosis enhance TGFβ signaling and responses

Chun Lin Chen, Wei Hsien Hou, I. Hua Liu, George Hsiao, Shuan Shian Huang, Jung San Huang

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

Clathrin-dependent endocytosis is believed to be involved in TGFβ-stimulated cellular responses, but the subcellular locus at which TGFβ 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 TGFβ and promote colocalization and accumulation of TβR-I and SARA at the plasma membrane. These inhibitors enhance TGFβ-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 TGFβ. Dynasore ameliorates atherosclerosis in the aortic endothelium of hypercholesterolemic ApoE-null mice by counteracting the suppressed TGFβ responsiveness caused by the hypercholesterolemia, presumably acting through its effect on TGFβ endocytosis and signaling in vascular cells.

Original languageEnglish
Pages (from-to)1863-1871
Number of pages9
JournalJournal of Cell Science
Volume122
Issue number11
DOIs
Publication statusPublished - Jun 1 2009

Keywords

  • Atherosclerosis
  • Coated pit
  • Endocytosis inhibitor
  • Enhancer
  • Signaling
  • TGFβ

ASJC Scopus subject areas

  • Cell Biology

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