Endoglin regulation of Smad2 function mediates beclin1 expression and endothelial autophagy

Christopher C. Pan, Sanjay Kumar, Nirav Shah, Jeffrey C. Bloodworth, Lukas J.A.C. Hawinkels, Karthikeyan Mythreye, Dale G. Hoyt, Nam Y. Lee

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Autophagy is the targeted degradation of proteins and organelles critical for homeostasis and cell survival. Transforming growth factor β (TGF-β) differentially regulates autophagy in a context-specific manner, although the precise intracellular mechanisms remain less clear. Importantly, how TGF-β controls autophagic responses in endothelial cells (EC) during angiogenesis is unknown. Here we identified endoglin, an ECspecific TGF-β co-receptor essential for angiogenesis, as a key determinant of autophagy. Among the two opposing TGF-β Smad pathways in the EC system (Smad1/5/8 and Smad2/3), we found Smad2 as the major transcriptional regulator of autophagy that targets beclin1 (BECN1) gene expression. Smad2, but not Smad3, acts as a repressor upstream of the BECN1 promoter region. Overall, endoglin promotes autophagy by impeding Smad2 transcriptional repressor activity. Notably, increased beclin1 levels upon Smad2 knockdown directly correlated with enhanced autophagy during angiogenesis. Taken together, these results establish endoglin as a critical mediator of autophagy and demonstrate a new transcriptional mechanism by which Smad2 inhibits angiogenesis.

Original languageEnglish (US)
Pages (from-to)14884-14892
Number of pages9
JournalJournal of Biological Chemistry
Volume290
Issue number24
DOIs
StatePublished - Jun 12 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Endoglin regulation of Smad2 function mediates beclin1 expression and endothelial autophagy'. Together they form a unique fingerprint.

  • Cite this

    Pan, C. C., Kumar, S., Shah, N., Bloodworth, J. C., Hawinkels, L. J. A. C., Mythreye, K., Hoyt, D. G., & Lee, N. Y. (2015). Endoglin regulation of Smad2 function mediates beclin1 expression and endothelial autophagy. Journal of Biological Chemistry, 290(24), 14884-14892. https://doi.org/10.1074/jbc.M114.630178