The functions of auxilin and Rab11 in Drosophila suggest that the fundamental role of ligand endocytosis in notch signaling cells is not recycling.
The functions of auxilin and Rab11 in Drosophila suggest that the fundamental role of ligand endocytosis in notch signaling cells is not recycling.
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DOI：
10.1371/journal.pone.0018259
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发表时间：
2011-03-23
期刊：
影响因子：
3.7
通讯作者：
Fischer JA
中科院分区：
文献类型：
--
作者：
Banks SM;Cho B;Eun SH;Lee JH;Windler SL;Xie X;Bilder D;Fischer JA
Notch信号需要信号发送细胞将配体内在化。两种内吞蛋白，epsin和auxilin，是配体内化和信号传导所必需的。Epsin促进网格蛋白包被的囊泡形成，而auxilin将网格蛋白从新内化的囊泡中剥离。提出了两种假说来解释配体内吞作用的必要性。一种观点认为，在配体/受体结合后，配体内吞作用通过拉动受体导致受体激活，这要么暴露细胞外区域的切割位点，要么解离两个受体亚基。或者，配体在受体结合之前内化，然后通过内体途径运输，再循环到质膜，可能会激活配体。激活可能意味着配体修饰或配体胞吞作用到有利于信号传导的膜环境。支持循环模型的一个关键证据是信号细胞对Rab11的需求，Rab11编码一种对内体循环至关重要的GTPase。在这里，我们使用果蝇Rab11和辅助素突变体来验证配体循环假说。首先，我们发现Rab11在眼盘的几个Notch信号事件中是必不可少的。其次，我们发现果蝇雌性生殖系细胞，一种已知不需要网格蛋白发出信号的细胞类型，也不需要辅助素来发出信号。第三，我们发现在Notch信号中对辅助素的大部分需求被网格蛋白重链和epsin的过表达所绕过。因此，辅助素在Notch信号传导中的主要作用不是产生无包被的含配体囊泡，而是维持游离网格蛋白池。综上所述，这些结果有力地表明，至少在某些细胞类型中，Notch配体内吞作用的主要功能不是配体再循环。
Notch signaling requires ligand internalization by the signal sending cells. Two endocytic proteins, epsin and auxilin, are essential for ligand internalization and signaling. Epsin promotes clathrin-coated vesicle formation, and auxilin uncoats clathrin from newly internalized vesicles. Two hypotheses have been advanced to explain the requirement for ligand endocytosis. One idea is that after ligand/receptor binding, ligand endocytosis leads to receptor activation by pulling on the receptor, which either exposes a cleavage site on the extracellular domain, or dissociates two receptor subunits. Alternatively, ligand internalization prior to receptor binding, followed by trafficking through an endosomal pathway and recycling to the plasma membrane may enable ligand activation. Activation could mean ligand modification or ligand transcytosis to a membrane environment conducive to signaling. A key piece of evidence supporting the recycling model is the requirement in signaling cells for Rab11, which encodes a GTPase critical for endosomal recycling. Here, we use Drosophila Rab11 and auxilin mutants to test the ligand recycling hypothesis. First, we find that Rab11 is dispensable for several Notch signaling events in the eye disc. Second, we find that Drosophila female germline cells, the one cell type known to signal without clathrin, also do not require auxilin to signal. Third, we find that much of the requirement for auxilin in Notch signaling was bypassed by overexpression of both clathrin heavy chain and epsin. Thus, the main role of auxilin in Notch signaling is not to produce uncoated ligand-containing vesicles, but to maintain the pool of free clathrin. Taken together, these results argue strongly that at least in some cell types, the primary function of Notch ligand endocytosis is not for ligand recycling.
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影响因子：
64.5
作者：
Emery, G;Hutterer, A;Knoblich, JA
通讯作者：
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作者：
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DOI：
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