Early endosomal regulation of Smad-dependent signaling in endothelial cells (Journal article)

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

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.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
Keywords: Animals,Carrier Proteins/physiology,Cattle,Cells, Cultured,DNA-Binding Proteins/*physiology,Endosomes/*physiology,Endothelium, Vascular/*physiology,Kinetics,Phosphorylation,Promoter Regions, Genetic,Receptors, Transforming Growth Factor beta/physiology,Signal Transduction/*physiology,Smad Proteins,Trans-Activators/*physiology,Zinc Fingers/physiology,rab5 GTP-Binding Proteins/genetics/metabolism
URI: http://olympias.lib.uoi.gr/jspui/handle/123456789/22294
ISSN: 0021-9258
Link: http://www.ncbi.nlm.nih.gov/pubmed/11877415
Appears in Collections:Άρθρα σε επιστημονικά περιοδικά ( Ανοικτά)

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