Different routes of bone morphogenic protein (BMP) receptor endocytosis influence BMP signaling
Different routes of bone morphogenic protein (BMP) receptor endocytosis influence BMP signaling
复制标题
DOI：
10.1128/mcb.00022-06
复制
发表时间：
2006-10-01
影响因子：
5.3
通讯作者：
Knaus, Petra
中科院分区：
文献类型：
--
作者：
Hartung, Anke;Bitton-Worms, Keren;Knaus, Petra
内吞作用对于真核细胞中的多种功能是重要的，包括通过跨膜受体调节信号级联。骨形态发生蛋白（BMP）受体I型（BRI）和H型（BRII）的内化及其与信号传导的关系在很大程度上尚未探索。在这里，我们表明，这两种受体类型通过网格蛋白包被的坑（CCP）进行组成性内吞作用，但只有BRII也经历小窝样内化。使用几种互补的方法，我们可以证明：（i）BMP-2介导的Smad 1/5磷酸化发生在非筏区域的质膜上，（ii）Smad信号传导的持续导致转录反应需要通过网格蛋白介导的途径进行内吞作用，以及（iii）BMP信号传导导致碱性磷酸酶诱导从受体开始，这些受体断裂成富含胆固醇的抗洗涤剂膜。此外，我们表明，BRII与Eps 15 R，CCP的组成部分，并与小窝蛋白-1，小窝的标记蛋白相互作用。两者合计，BMP受体在不同的膜结构域的本地化是先决条件，他们采取不同的内吞途径与Smad依赖性和Smad非依赖性信号级联的具体影响。
Endocytosis is important for a variety of functions in eukaryotic cells, including the regulation of signaling cascades via transmembrane receptors. The internalization of bone morphogenetic protein (BMP) receptor type I (BRI) and type H (BRII) and its relation to signaling were largely unexplored. Here, we demonstrate that both receptor types undergo constitutive endocytosis via clathrin-coated pits (CCPs) but that only BRII undergoes also caveola-like internalization. Using several complementary approaches, we could show that (i) BMP-2-mediated Smad1/5 phosphorylation occurs at the plasma membrane in nonraft regions, (ii) continuation of Smad signaling resulting in a transcriptional response requires endocytosis via the clathrin-mediated route, and (iii) BMP signaling leading to alkaline phosphatase induction initiates from receptors that fractionate into cholesterol-enriched, detergent-resistant membranes. Furthermore, we show that BRII interacts with Eps15R, a constitutive component of CCPs, and with caveolin-1, the marker protein of caveolae. Taken together, the localization of BMP receptors in distinct membrane domains is prerequisite to their taking different endocytosis routes with specific impacts on Smad-dependent and Smad-independent signaling cascades.