BMP signaling requires retromer-dependent recycling of the type I receptor
BMP signaling requires retromer-dependent recycling of the type I receptor
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DOI：
10.1073/pnas.1319947111
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发表时间：
2014-02-18
影响因子：
11.1
通讯作者：
Padgett, Richard W.
中科院分区：
文献类型：
--
作者：
Gleason, Ryan J.;Akintobi, Adenrele M.;Padgett, Richard W.
信号通路的转化生长因子β（TGF β）超家族，包括配体和受体的骨形态发生蛋白（BMP）亚家族，控制着后生动物生物学中的无数发育过程。已经提出受体从质膜到内体的转运促进TGF β信号转导并在整个发育过程中形成BMP信号梯度。然而，BMP受体的内吞后运输如何促进信号转导的调节仍然是个谜。在这里，我们报告说，秀丽隐杆线虫BMP I型受体SMA-6（小-6）的细胞内结构域结合到retromer复合物，并在retromer突变体，SMA-6被降解，因为它的错配溶酶体。令人惊讶的是，我们发现，II型BMP受体，dauer-4（dauer形成缺陷-4），是逆转录酶独立的，并通过一个独特的途径介导的ARF-6（ADP-核糖基化因子-6）。重要的是，我们发现逆转录酶的缺失阻断了多种组织中的BMP信号传导。总之，我们的研究结果表明，在受体再循环过程中分离I型和II型受体的机制，可能终止信号传导，同时保留两种受体进行进一步的激活。
The transforming growth factor beta (TGF beta) superfamily of signaling pathways, including the bone morphogenetic protein (BMP) subfamily of ligands and receptors, controls a myriad of developmental processes across metazoan biology. Transport of the receptors from the plasma membrane to endosomes has been proposed to promote TGF beta signal transduction and shape BMP-signaling gradients throughout development. However, how postendocytic trafficking of BMP receptors contributes to the regulation of signal transduction has remained enigmatic. Here we report that the intracellular domain of Caenorhabditis elegans BMP type I receptor SMA-6 (small-6) binds to the retromer complex, and in retromer mutants, SMA-6 is degraded because of its missorting to lysosomes. Surprisingly, we find that the type II BMP receptor, DAF-4 (dauer formation-defective-4), is retromer-independent and recycles via a distinct pathway mediated by ARF-6 (ADP-ribosylation factor-6). Importantly, we find that loss of retromer blocks BMP signaling in multiple tissues. Taken together, our results indicate a mechanism that separates the type I and type II receptors during receptor recycling, potentially terminating signaling while preserving both receptors for further rounds of activation.