Distinct endocytic responses of heteromeric and homomeric transforming growth factor beta receptors
Distinct endocytic responses of heteromeric and homomeric transforming growth factor beta receptors
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DOI：
10.1091/mbc.8.11.2133
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发表时间：
1997-11-01
影响因子：
3.3
通讯作者：
Leof, EB
中科院分区：
文献类型：
--
作者：
Anders, RA;Arline, SL;Leof, EB
转化生长因子β（TGF β）家族配体启动能够调节细胞生长和分化的级联事件。负责转导这些细胞信号的受体被称为I型和II型TGF β受体。配体与II型受体的结合导致I型受体的转磷酸化和活化。然后，该异聚复合物将信号传播到下游效应物。目前关于TGF β受体在配体结合后的命运的数据很少，相互矛盾的报道表明细胞表面受体数量没有变化或减少。为了解决配体激活受体的命运，我们使用了我们先前表征的嵌合受体，其由来自粒细胞/巨噬细胞集落刺激因子α或β受体的配体结合结构域与I型或II型TGF β受体的跨膜和胞质结构域融合组成。该系统不仅提供了必要的灵敏度和特异性来解决这些类型的问题，而且还允许区分对同源或异源胞内TGF β受体寡聚化的内吞反应。提供的数据显示，在配体结合的几分钟内，嵌合TGF β受体被内化。然而，尽管所有嵌合受体组合显示相似的内化率，但受体下调仅在异聚TGF β受体活化后发生。这些结果表明，有效的受体下调需要I型和II型TGF β受体之间的串扰，并且TGF β受体异聚体和同聚体显示出不同的运输行为。
Transforming growth factor beta (TGF beta) family ligands initiate a cascade of events capable of modulating cellular growth and differentiation. The receptors responsible for transducing these cellular signals are referred to as the type I and type II TGF beta receptors. Ligand binding to the type II receptor results in the transphosphorylation and activation of the type I receptor. This heteromeric complex then propagates the signal(s) to downstream effectors. There is presently little data concerning the fate of TGF beta receptors after ligand binding, with conflicting reports indicating no change or decreasing cell surface receptor numbers. To address the fate of ligand-activated receptors, we have used our previously characterized chimeric receptors consisting of the ligand binding domain from the granulocyte/macrophage colony-stimulating factor alpha or beta receptor fused to the transmembrane and cytoplasmic domain of the type I or type II TGF beta receptor. This system not only provides the necessary sensitivity and specificity to address these types of questions but also permits the differentiation of endocytic responses to either homomeric or heteromeric intracellular TGF beta receptor oligomerization. Data are presented that show, within minutes of ligand binding, chimeric TGF beta receptors are internalized. However, although all the chimeric receptor combinations show similar internalization rates, receptor down-regulation occurs only after activation of heteromeric TGF beta receptors. These results indicate that effective receptor down-regulation requires cross-talk between the type I and type II TGF beta receptors and that TGF beta receptor heteromers and homomers show distinct trafficking behavior.