Mechanisms of transforming growth factor-β receptor endocytosis and intracellular sorting differ between fibroblasts and epithelial cells
Mechanisms of transforming growth factor-β receptor endocytosis and intracellular sorting differ between fibroblasts and epithelial cells
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DOI：
10.1091/mbc.12.3.675
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发表时间：
2001-03-01
影响因子：
3.3
通讯作者：
Leof, EB
中科院分区：
文献类型：
--
作者：
Dore, JJE;Yao, DY;Leof, EB
转化生长因子-β (TGF-β) 是多功能蛋白质，能够刺激或抑制有丝分裂，具体取决于细胞类型。这些不同的细胞反应是通过刺激由 I 型和 II 型受体组成的单一受体复合物引起的。使用嵌合受体模型，其中粒细胞/单核细胞集落刺激因子受体配体结合结构域与TGF-β I型和II型受体的跨膜和细胞质信号传导结构域融合，我们希望描述特定氨基酸残基在调节成纤维细胞和成纤维细胞中配体介导的内吞作用和信号传导中的作用 上皮细胞。在 I 型受体的 Y182、T200 和 Y249 以及 II 型受体的 K277 和 P525 处引入了特定的点突变。 Y182 或 Y249（两个假定的共有酪氨酸内化基序内的残基）的突变对内吞作用或信号传导没有影响。这与 T200 突变为缬氨酸形成对比，后者导致两种细胞类型中的信号传导消除，而仅消除成纤维细胞中受体的下调。此外，在没有配体的情况下，成纤维细胞和上皮细胞都会持续内化TGF-β受体复合物并将其再循环回质膜。这些数据表明间充质细胞和上皮细胞在内吞分选方面存在根本差异，并表明配体结合将异聚受体从默认回收池转移到介导受体下调和信号传导的途径。
Transforming growth factor-betas (TGF-beta) are multifunctional proteins capable of either stimulating or inhibiting mitosis, depending on the cell type. These diverse cellular responses are caused by stimulating a single receptor complex composed of type I and type II receptors. Using a chimeric receptor model where the granulocyte/monocyte colony-stimulating factor receptor ligand binding domains are fused to the transmembrane and cytoplasmic signaling domains of the TGF-beta type I and II receptors, we wished to describe the role(s) of specific amino acid residues in regulating ligand-mediated endocytosis and signaling in fibroblasts and epithelial cells. Specific point mutations were introduced at Y182, T200, and Y249 of the type I receptor and K277 and P525 of the type II receptor. Mutation of either Y182 or Y249, residues within two putative consensus tyrosine-based internalization motifs, had no effect on endocytosis or signaling. This is in contrast to mutation of T200 to valine, which resulted in ablation of signaling in both cell types, while only abolishing receptor down-regulation in fibroblasts. Moreover, in the absence of ligand, both fibroblasts and epithelial cells constitutively internalize and recycle the TGF-beta receptor complex back to the plasma membrane. The data indicate fundamental differences between mesenchymal and epithelial cells in endocytic sorting and suggest that ligand binding diverts heteromeric receptors from the default recycling pool to a pathway mediating receptor down-regulation and signaling.