Early endosomal regulation of Smad-dependent signaling in endothelial cells

E. Panopoulou, D. J. Gillooly, J. L. Wrana, M. Zerial, H. Stenmark, C. Murphy, T. Fotsis

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117 Citations (Scopus)


Transforming growth factor beta (TGFbeta) receptors require SARA for phosphorylation of the downstream transducing Smad proteins. SARA, a FYVE finger protein, binds to membrane lipids suggesting that activated receptors may interact with downstream signaling molecules at discrete endocytic locations. In the present study, we reveal a critical role for the early endocytic compartment in regulating Smad-dependent signaling. Not only is SARA localized on early endosomes, but also its minimal FYVE finger sequence is sufficient for early endosomal targeting. Expression of a SARA mutant protein lacking the FYVE finger inhibits downstream activin A signaling in endothelial cells. Moreover, a dominant-negative mutant of Rab5, a crucial protein for early endosome dynamics, causes phosphorylation and nuclear translocation of Smads leading to constitutive (i.e. ligand independent) transcriptional activation of a Smad-dependent promoter in endothelial cells. As inhibition of endocytosis using the K44A negative mutant of dynamin and RN-tre did not lead to activation of Smad-dependent transcription, the effects of the dominant-negative Rab5 are likely to be a consequence of altered membrane trafficking of constitutively formed TGFbeta/activin type I/II receptor complexes at the level of early endosomes. The results suggest an important interconnection between early endosomal dynamics and TGFbeta/activin signal transduction pathways.
Original languageEnglish
Pages (from-to)18046-52
JournalJournal of Biological Chemistry
Publication statusPublished - 4 Mar 2002

Bibliographical note

M1 - 20


  • Animal Carrier Proteins/physiology Cattle Cells, Cultured DNA-Binding Proteins/*physiology Endosomes/*physiology Endothelium, Vascular/*physiology Kinetics Phosphorylation Promoter Regions (Genetics) Receptors, Transforming Growth Factor beta/physiology Signal Transduction/*physiology Support, Non-U.S. Gov't Trans-Activators/*physiology Zinc Fingers/physiology rab5 GTP-Binding Proteins/genetics/metabolism


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