The Transforming Growth Factor-β Type III Receptor Mediates Distinct Subcellular Trafficking and Downstream Signaling of Activin-like Kinase (ALK)3 and ALK6 Receptors
The Transforming Growth Factor-β Type III Receptor Mediates Distinct Subcellular Trafficking and Downstream Signaling of Activin-like Kinase (ALK)3 and ALK6 Receptors
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DOI：
10.1091/mbc.e09-07-0539
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发表时间：
2009-10-15
影响因子：
3.3
通讯作者：
Blobe, Gerard C.
中科院分区：
文献类型：
--
作者：
Lee, Nam Y.;Kirkbride, Kellye C.;Blobe, Gerard C.
骨形态发生蛋白（BMP）通过BMP I型和II型受体发出信号来调节细胞过程，包括胚胎发育。I型BMP受体激活素样激酶（ALK）3和ALK 6具有高度同源性，但具有不同的信号传导作用。在这里，我们报告说，虽然转化生长因子（TGF）-β III型受体（T β RIII）增强ALK 3和ALK 6信号，T β RIII更有力地增强ALK 6介导的刺激BMP反应性启动子XVent 2和3GC 2，并上调早期反应基因Smad 6。相反，T β RIII特异性增强ALK 3介导的早期反应基因ID-1的上调。T β RIII主要通过其细胞外结构域与ALK 3结合，而其与ALK 6的相互作用需要细胞外和细胞质结构域。T β RIII，沿着其相互作用的支架蛋白β-抑制蛋白2，诱导ALK 6的内化。相反，T β RIII与ALK 3共定位并导致ALK 3的细胞表面保留，而不依赖于β-arrestin 2。尽管T β RIII、ALK 6和β-arrestin 2之间的复合物形成以及T β RIII/ALK 6内化导致最大BMP信号传导，但不能与β-arrestin 2相互作用的T β RIII突变体T β RIII-T841 A不能这样做。这些研究支持T β RIII在介导差异ALK 3和ALK 6亚细胞运输中的新作用，导致ALK 3和ALK 6下游的不同信号传导。
Bone morphogenetic proteins (BMPs) signal through the BMP type I and type II receptors to regulate cellular processes, including embryonic development. The type I BMP receptors activin-like kinase (ALK)3 and ALK6 share a high degree of homology, yet possess distinct signaling roles. Here, we report that although the transforming growth factor (TGF)-beta type III receptor (T beta RIII) enhanced both ALK3 and ALK6 signaling, T beta RIII more potently enhanced ALK6-mediated stimulation of the BMP-responsive promoters XVent2 and 3GC2, and up-regulation of the early response gene Smad6. In contrast, T beta RIII specifically enhanced ALK3-mediated up-regulation of the early response gene ID-1. T beta RIII associated with ALK3 primarily through their extracellular domains, whereas its interaction with ALK6 required both the extracellular and cytoplasmic domains. T beta RIII, along with its interacting scaffolding protein beta-arrestin2, induced the internalization of ALK6. In contrast, T beta RIII colocalized with and resulted in the cell surface retention of ALK3, independently of beta-arrestin2. Although complex formation between T beta RIII, ALK6, and beta-arrestin2 and T beta RIII/ALK6 internalization resulted in maximal BMP signaling, the T beta RIII mutant unable to interact with beta-arrestin2, T beta RIII-T841A, was unable to do so. These studies support a novel role for T beta RIII in mediating differential ALK3 and ALK6 subcellular trafficking resulting in distinct signaling downstream of ALK3 and ALK6.