Waksman Institute of Microbiology, Department of Molecular Biology and Biochemistry, and Cancer Institute of New Jersey, Rutgers University, Piscataway, NJ 08854-8020.
Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2578-83. doi: 10.1073/pnas.1319947111. Epub 2014 Feb 3.
The transforming growth factor β (TGFβ) 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 TGFβ 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.
转化生长因子 β (TGFβ) 信号通路超家族，包括骨形态发生蛋白 (BMP) 配体和受体亚家族，控制着后生动物生物学中无数的发育过程。受体从质膜向内体的运输被认为可以促进 TGFβ 信号转导，并在整个发育过程中塑造 BMP 信号梯度。然而，BMP 受体的内体后转运如何调节信号转导仍然是个谜。在这里，我们报告秀丽隐杆线虫 BMP Ⅰ型受体 SMA-6（小-6）的细胞内域与逆行转运体复合物结合，在逆行转运体突变体中，由于 SMA-6 错误分拣到溶酶体中，因此会被降解。令人惊讶的是，我们发现 II 型 BMP 受体 DAF-4（持续形成缺陷-4）是逆行转运体非依赖性的，并且通过 ARF-6（ADP-核糖基化因子-6）介导的独特途径进行循环。重要的是，我们发现逆行转运体的缺失会阻断多种组织中的 BMP 信号。总之，我们的结果表明了一种在受体循环过程中分离 I 型和 II 型受体的机制，该机制可能在保留受体以备进一步激活的同时终止信号。
