Requirement of Smurf-mediated endocytosis of Patched1 in sonic hedgehog signal reception.
Requirement of Smurf-mediated endocytosis of Patched1 in sonic hedgehog signal reception.
复制标题
声波刺猬信号接收中 Smurf 介导的 Patched1 内吞作用的要求。
DOI：
10.7554/elife.02555
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发表时间：
2014-06-12
期刊：
影响因子：
7.7
通讯作者：
Cheng SY
中科院分区：
文献类型：
--
作者：
Yue S;Tang LY;Tang Y;Tang Y;Shen QH;Ding J;Chen Y;Zhang Z;Yu TT;Zhang YE;Cheng SY
音猬因子（Shh）在细胞表面的接收必须确保分级的形态发生信号能在邻近细胞中得到相应的解读，从而在发育过程中确定组织模式。在此，我们报道了受体patched1（Ptch1）的内吞分选信号，其包含两个“PPXY”基序，这些信号引导Ptch1在溶酶体中降解。这些信号可被两个HECT结构域的泛素E3连接酶Smurf1和Smurf2识别，它们受Shh诱导，并与Ptch1结合后在小窝蛋白 - 1脂质筏中富集。Smurf介导的Ptch1内吞周转对于其从初级纤毛的清除以及通路激活至关重要。去除两种Smurf蛋白会完全消除Shh维持小脑出生后颗粒细胞前体增殖的能力。这些发现揭示了Shh通路激活中的一个新步骤，它是Ptch1负反馈回路的一部分，可精确控制对Shh梯度信号作出响应的信号输出。
DOI: http://dx.doi.org/10.7554/eLife.02555.001
音猬蛋白在发育过程中对多细胞生物体身体结构的建立起着许多重要作用。在成年生物体中，它调节维持器官和组织的干细胞。在胚胎中，音猬蛋白由某些细胞分泌以形成浓度梯度；细胞随后测量该浓度以确定自身位置，从而使其能够发育成正确类型的细胞。然而，这一过程的许多细节尚未完全清楚。
这一过程的核心是音猬蛋白、质膜上的一种名为patched1的受体以及另一种名为Smoothened的膜蛋白之间的相互作用。Smoothened的作用是激活进入细胞核的蛋白质并“开启”该通路的靶基因，这些基因编码patched1和许多其他蛋白质。另一方面，patched1的作用是抑制Smoothened。然而，当音猬蛋白与patched1结合时，后者无法抑制Smoothened。
增加patched1的产生被认为有两个主要作用：它阻止音猬蛋白通路的激活，并防止音猬蛋白扩散到邻近细胞（通过与之结合）。但是patched1自身的水平是如何被调节的呢？岳等人现在报道在哺乳动物细胞中，两种名为Smurf1和Smurf2的蛋白质起到了这种调节作用。
Smurf1和Smurf2是将一种名为泛素的分子连接到蛋白质上的酶，从而引发一系列导致蛋白质降解的事件。岳等人现在表明Smurf1和Smurf2识别patched1上的一个信号并进行类似的修饰，导致patched1通过另一种途径被内化并在溶酶体中降解。这一系列事件最终使音猬蛋白通路得以激活。
岳等人的工作揭示了一个关键的酶促步骤，该步骤将未结合音猬蛋白的patched1受体与那些已结合的受体区分开来。需要进一步的研究来确定是否可以为了治疗目的而操纵这一信号通路。
DOI: http://dx.doi.org/10.7554/eLife.02555.002
Cell surface reception of Sonic hedgehog (Shh) must ensure that the graded morphogenic signal is interpreted accordingly in neighboring cells to specify tissue patterns during development. Here, we report endocytic sorting signals for the receptor Patched1 (Ptch1), comprising two ‘PPXY’ motifs, that direct it to degradation in lysosomes. These signals are recognized by two HECT-domain ubiquitin E3 ligases, Smurf1 and Smurf2, which are induced by Shh and become enriched in Caveolin-1 lipid rafts in association with Ptch1. Smurf-mediated endocytic turnover of Ptch1 is essential for its clearance from the primary cilium and pathway activation. Removal of both Smurfs completely abolishes the ability of Shh to sustain the proliferation of postnatal granule cell precursors in the cerebellum. These findings reveal a novel step in the Shh pathway activation as part of the Ptch1 negative feedback loop that precisely controls the signaling output in response to Shh gradient signal. DOI: http://dx.doi.org/10.7554/eLife.02555.001 Sonic hedgehog protein fulfils many vital roles in establishing the body plan of multicellular organisms during development. And in adult organisms it regulates the stem cells that maintain organs and tissues. In the embryo, Sonic hedgehog is secreted by certain cells to create a concentration gradient; cells then measure this concentration to work out where they are, which allows them to develop into the right sort of cells. However, many details of this process are not completely understood. At the core of this process are the interactions between the Sonic hedgehog protein, a receptor called Patched1 that is found on plasma membranes, and another membrane protein called Smoothened. The job of Smoothened is to activate proteins that enter the cell nucleus and ‘switch on’ the pathway's target genes, which encode Patched1 and a number of other proteins. The role of Patched1, on the other hand, is to repress Smoothened. However, when sonic hedgehog binds to Patched1, the latter is unable to repress Smoothened. Increasing the production of Patched1 is thought to serve two main roles: it prevents activation of the Sonic hedgehog pathway, and it prevents the Sonic hedgehog protein spreading to neighboring cells (by binding to it). But how is the level of Patched1 itself regulated? Yue et al. now report that two proteins, called Smurf1 and Smurf2, perform this regulation role in mammalian cells. Smurf1 and Smurf2 are enzymes that attach a molecule called ubiquitin to proteins, setting in train a series of events that leads to the degradation of the protein. Yue et al. now show that Smurf1 and Smurf2 recognize a signal on Patched1 and perform a similar modification, causing the Patched1 to be internalized through an alternate pathway and degraded in lysosomes. This series of events ultimately allow the Sonic hedgehog pathway to be activated. The work of Yue et al. exposes a critical enzymatic step that sorts unbound Patched1 receptors from those that are bound to Sonic hedgehog proteins. Further research is needed to determine if this signaling pathway can be manipulated for therapeutic purposes. DOI: http://dx.doi.org/10.7554/eLife.02555.002