Endocytosis of the Type III Transforming Growth Factor-β (TGF-β) Receptor through the Clathrin-independent/Lipid Raft Pathway Regulates TGF-β Signaling and Receptor Down-regulation
Endocytosis of the Type III Transforming Growth Factor-β (TGF-β) Receptor through the Clathrin-independent/Lipid Raft Pathway Regulates TGF-β Signaling and Receptor Down-regulation
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DOI：
10.1074/jbc.m804741200
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发表时间：
2008-12-12
影响因子：
4.8
通讯作者：
Blobe, Gerard C.
中科院分区：
文献类型：
--
作者：
Finger, Elizabeth C.;Lee, Nam Y.;Blobe, Gerard C.
转化生长因子-β通过三种高度保守的细胞表面受体，即III型转化生长因子-β受体(T-βRIII)、II型转化生长因子-β受体(T-βRII)和I型转化生长因子-β受体(T-βRI)，调节细胞的增殖、分化、迁移和凋亡等多种细胞过程。虽然TβRI和TβRII都通过网织蛋白介导的内吞作用进行配体非依赖性的内吞作用，导致信号增强，但TβRIII内吞作用的机制和功能尚不清楚。TβRIII是一种具有较短细胞质尾巴的硫酸乙酰肝素蛋白多糖，作为转化生长因子-β超家族共受体发挥作用，通过尚未完全确定的机制参与转化生长因子-β信号转导。我们以前已经报道，TβRIII内吞通过与β-arrestin-2的一种新的相互作用而导致转化生长因子-β信号的减少。在这里，我们证明了TβRIII在配体和糖胺多聚糖修饰非依赖性和胞浆区域依赖的方式进行内吞作用，与TβRIII胞浆区域的Thr-841与β-arrestin2促进TβRIII内吞作用相互作用。TβRIII既经历网状蛋白介导的内吞作用，又经历网状蛋白非依赖的内吞作用。重要的是，抑制网状蛋白非依赖的脂筏途径，而不是抑制网状蛋白依赖的途径，导致转化生长因子-β1诱导的Smad2和p38磷酸化减少，支持TβRIII的网状蛋白非依赖性内吞在调节Smad依赖和Smad非依赖性的转化生长因子-β信号中的特定作用。
Transforming growth factor-beta(TGF-beta) signals through three highly conserved cell surface receptors, the type III TGF-beta receptor (T beta RIII), the type II TGF-beta receptor (T beta RII), and the type I TGF-beta receptor (T beta RI) to regulate diverse cellular processes including cell proliferation, differentiation, migration, and apoptosis. Although T beta RI and T beta RII undergo ligand-independent endocytosis by both clathrin-mediated endocytosis, resulting in enhanced signaling, and clathrin-independent endocytosis, resulting in receptor degradation, the mechanism and function of T beta RIII endocytosis is poorly understood. T beta RIII is a heparan sulfate proteoglycan with a short cytoplasmic tail that functions as a TGF-beta superfamily co-receptor, contributing to TGF-beta signaling through mechanisms yet to be fully defined. We have reported previously that T beta RIII endocytosis, mediated by a novel interaction with beta arrestin-2, results in decreased TGF-beta signaling. Here we demonstrate that T beta RIII undergoes endocytosis in a ligand and glycosaminoglycan modification-independent and cytoplasmic domain-dependent manner, with the interaction of Thr-841 in the cytoplasmic domain of T beta RIII with beta-arrestin2 enhancing T beta RIII endocytosis. T beta RIII undergoes both clathrin-mediated and clathrin-independent endocytosis. Importantly, inhibition of the clathrin-independent, lipid raft pathway, but not of the clathrin-dependent pathway, results in decreased TGF-beta 1 induced Smad2 and p38 phosphorylation, supporting a specific role for clathrin-independent endocytosis of T beta RIII in regulating both Smad-dependent and Smad-independent TGF-beta signaling.