ALK1 regulates the internalization of endoglin and the type III TGF-β receptor

Mol Biol Cell. 2021 Apr 1;32(7):605-621. doi: 10.1091/mbc.E20-03-0199. Epub 2021 Feb 10.


Complex formation and endocytosis of transforming growth factor-β (TGF-β) receptors play important roles in signaling. However, their interdependence remained unexplored. Here, we demonstrate that ALK1, a TGF-β type I receptor prevalent in endothelial cells, forms stable complexes at the cell surface with endoglin and with type III TGF-β receptors (TβRIII). We show that ALK1 undergoes clathrin-mediated endocytosis (CME) faster than ALK5, type II TGF-β receptor (TβRII), endoglin, or TβRIII. These complexes regulate the endocytosis of the TGF-β receptors, with a major effect mediated by ALK1. Thus, ALK1 enhances the endocytosis of TβRIII and endoglin, while ALK5 and TβRII mildly enhance endoglin, but not TβRIII, internalization. Conversely, the slowly endocytosed endoglin has no effect on the endocytosis of either ALK1, ALK5, or TβRII, while TβRIII has a differential effect, slowing the internalization of ALK5 and TβRII, but not ALK1. Such effects may be relevant to signaling, as BMP9-mediated Smad1/5/8 phosphorylation is inhibited by CME blockade in endothelial cells. We propose a model that links TGF-β receptor oligomerization and endocytosis, based on which endocytosis signals are exposed/functional in specific receptor complexes. This has broad implications for signaling, implying that complex formation among various receptors regulates their surface levels and signaling intensities.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / metabolism*
  • Activin Receptors, Type II / physiology
  • Animals
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • Endocytosis
  • Endoglin / metabolism*
  • Endoglin / physiology
  • Endothelial Cells / metabolism
  • Humans
  • Phosphorylation
  • Protein Binding
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteoglycans / metabolism*
  • Proteoglycans / physiology
  • Receptor, Transforming Growth Factor-beta Type I / metabolism
  • Receptor, Transforming Growth Factor-beta Type II / metabolism
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Receptors, Transforming Growth Factor beta / physiology
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism


  • ENG protein, human
  • Endoglin
  • Proteoglycans
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • betaglycan
  • Protein-Serine-Threonine Kinases
  • ACVRL1 protein, human
  • Activin Receptors, Type II
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • TGFBR1 protein, human
  • TGFBR2 protein, human