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

Keren Tazat, Leslie Pomeraniec-Abudy, Melissa Hector-Greene, Szabina Szófia Szilágyi, Swati Sharma, Elise M. Cai, Armando L. Corona, Marcelo Ehrlich, Gerard C. Blobe, Yoav I. Henis

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)605-621
Number of pages17
JournalMolecular Biology of the Cell
Volume32
Issue number7
DOIs
StatePublished - 1 Apr 2021

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