ALK1 regulates the internalization of endoglin and the type III TGF-β receptor.
ALK1 regulates the internalization of endoglin and the type III TGF-β receptor.
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DOI：
10.1091/mbc.e20-03-0199
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发表时间：
2021-04-01
影响因子：
3.3
通讯作者：
Henis YI
中科院分区：
文献类型：
--
作者：
Tazat K;Pomeraniec-Abudy L;Hector-Greene M;Szilágyi SS;Sharma S;Cai EM;Corona AL;Ehrlich M;Blobe GC;Henis YI
转化生长因子-β（transforming growth factor-β，TGF-β）受体的复合物形成和内吞作用在信号转导中起重要作用。然而，它们之间的相互依存关系仍未得到探讨。在这里，我们证明了ALK 1，一种在内皮细胞中普遍存在的TGF-β I型受体，在细胞表面与内皮糖蛋白和III型TGF-β受体（TβRIII）形成稳定的复合物。我们发现，ALK 1经历网格蛋白介导的内吞作用（CME）比ALK 5，II型TGF-β受体（TβRII），内皮糖蛋白或TβRIII更快。这些复合物调节TGF-β受体的内吞作用，主要作用由ALK 1介导。因此，ALK 1可增强TβRIII和endoglin的内吞作用，而ALK 5和TβRII可轻度增强endoglin的内化，但不增强TβRIII的内化。相反，缓慢内吞的内皮素对ALK 1、ALK 5或TβRII的内吞没有影响，而TβRIII具有不同的影响，减缓ALK 5和TβRII的内化，但不减缓ALK 1的内化。这种作用可能与信号传导有关，因为BMP 9介导的Smad 1/5/8磷酸化被内皮细胞中的CME阻断抑制。我们提出了一个模型，连接TGF-β受体寡聚化和内吞作用，基于内吞信号暴露/功能在特定的受体复合物。这对信号传导具有广泛的影响，意味着各种受体之间的复合物形成调节其表面水平和信号传导强度。
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.