刺猬信号通路

title: 发现.
content: 在20世纪70年代,发育生物学的基本问题是一个相对简单的受精卵是如何发展成一个复杂的身体分节的动物的。70年代末,克里斯汀·纽斯林-沃尔哈德和艾瑞克·威斯乔斯分离了控制果蝇前后体轴发育分节的突变基因,他们的“饱和诱变”技术导致了一系列参与体轴形态发生基因的发现。1995年,他们因在对果蝇胚胎发育基因突变的研究工作与爱德华·路易斯共同获得诺贝尔奖。  黑腹果蝇的刺猬 ("hh") 基因被发现为其中一种可以造成个体体节前后差异的重要基因。果蝇的刺猬基因在1992年分别被 Jym Mohler, Philip Beachy, 以及 Thomas B. Kornberg的实验室所复制出来。 若其中一些刺猬基因发生突变,将会造成相较于野生型来说,较为短小且矮胖的不正常形状胚胎。刺猬基因的功能为影响体节极性,其突变会会影响幼体的表皮棘刺和成体的附支,如腿和触角。Rather than the normal pattern of denticles, hedgehog mutant larvae tend to have "solid lawns" of denticles (Figure 1). 刺猬基因突变的果蝇幼虫具有短小且多毛的特征,形似刺猬,故此得名。
title: 果蝇.
title: 机制.
content: 昆虫细胞表达全长含有锌指的转录因子Ci蛋白, 而此蛋白会在细胞质中和类似kinesin蛋白Costal-2 (Cos2) 形成复合体并结合到微管上(图2)。 对155 kDa全长Ci蛋白的依赖于蛋白酶体的剪切产生75 kDa片段(CiR)。CiR在细胞内累计并扩散到细胞核,在那里它作为刺猬因子靶基因的共。 The steps leading to Ci protein proteolysis include phosphorylation of Ci protein by several protein kinases; PKA, GSK3β and CK1 (Figure 2). The "Drosophila" protein Slimb is part of an SCF complex that targets proteins for ubiquitylation. Slimb binds to phosphorylated Ci protein.  In the absence of Hh (图 3), a cell-surface transmembrane protein called Patched (PTCH) acts to prevent high expression and activity of a 7 membrane spanning receptor called Smoothened (SMO). Patched has sequence similarity to known membrane transport proteins. When extracellular Hh is present (Figure 3), it binds to and inhibits Patched, allowing Smoothened to accumulate and inhibit the proteolytic cleavage of the Ci protein. This process most likely involves the direct interaction of Smoothened and Costal-2 and may involve sequestration of the Ci protein-containing complex to a microdomain where the steps leading to Ci protein proteolysis are disrupted. The mechanism by which Hh binding to Patched leads to increased levels of Smoothened is not clear (Step 1 in Figure 3). Following binding of Hh to Patched, Smoothened levels increase greatly over the level maintained in cells when Patched is not bound to Hh. It has been suggested that phosphorylation of Smoothened plays a role in Hh-dependent regulation of Smoothened levels.  In cells with Hh-activated Patched (Figure 3), the intact Ci protein accumulates in the cell cytoplasm and levels of CiR decrease, allowing transcription of some genes such as decapentaplegic (dpp, a member of the BMP growth factor family). For other Hh-regulated genes, expression requires not only the loss of CiR but also the positive action of uncleaved Ci to act as a transcriptional activator. Costal-2 is normally important for holding Ci protein in the cytoplasm, but interaction of Smoothened with Costal-2 allows some intact Ci protein to go to the nucleus. The "Drosophila" protein Fused (Fu in Figure 3) is a protein kinase that binds to Costal-2. Fused can inhibit Suppressor of Fused (SUFU), which in turn interacts with Ci to regulate gene transcription in some cell types.
title: 作用.
content: Hedgehog has roles in larval body segment development and in formation of adult appendages. During the formation of body segments in the developing "Drosophila" embryo, stripes of cells that synthesize the transcription factor Engrailed can also express the cell-to-cell signaling protein Hedgehog (green in Figure 4). Hedgehog is not free to move very far from the cells that make it and so it only activates a thin stripe of cells adjacent to the Engrailed-expressing cells. When acting in this local fashion, hedgehog works as a paracrine factor. Only cells to one side of the Engrailed-expressing cells are competent to respond to Hedgehog following interaction of Hh with the receptor protein Patched (blue in Figure 4).  Cells with Hh-activated Patched receptor synthesize the Wingless protein (red in Figure 4). If a "Drosophila" embryo is altered so as to produce Hh in all cells, all of the competent cells respond and form a broader band of Wingless-expressing cells in each segment. The "wingless" gene has an upstream transcription regulatory region that binds the Ci transcription factor in a Hh-dependent fashion resulting in an increase in "wingless" transcription (interaction 2 in Figure 3) in a stripe of cells adjacent to the stripe of Hh-producing cells.  Wingless protein acts as an extracellular signal and patterns the adjacent rows of cells by activating its cell surface receptor Frizzled. Wingless acts on Engrailed-expressing cells to stabilize the stripes of Engrailed expression. Wingless is a member of the Wnt family of cell-to-cell signaling proteins. The reciprocal signaling by Hedgehog and Wingless stabilizes the boundary between parasegments (Figure 4, top). The effects of Wingless and Hedgehog on other stripes of cells in each segment establishes a positional code that accounts for the distinct anatomical features along the anterior-posterior axis of the segments  The Wingless protein is called "wingless" because of the phenotype of some "wingless" fly mutants. Wingless and Hedgehog functioned together during metamorphosis to coordinate wing formation. Hedgehog is expressed in the posterior part of developing "Drosophila" limbs. Hedgehog also participates in the coordination of eye, brain, gonad, gut and tracheal development. Hedgehog has been implicated in reduced eye development in the amphipod Gammarus minus. Specifically, downregulation of hedgehog results in reduced eyes.
title: 脊椎动物.
title: 人类疾病.
content: 胚胎发育时缺少刺猬因子(因基因突变或孕妇误食致畸剂)都会导致严重的发育异常。

Summary: 刺猬信号通路(英语:Hedgehog signaling pathway)是重要的信号传导通路。

Hedgehog-Signalweg: Der Hedgehog-Signalweg ist ein Signaltransduktionsweg, durch den Zellen auf äußere Signale reagieren können. Der Signalweg ist nach seinem Liganden "Hedgehog" (Hh) benannt, einem Signalprotein, das als lokales Morphogen eine wichtige Funktion bei der Embryonalentwicklung von Tieren einnimmt und in der Evolutionsgeschichte sehr früh auftrat. Eine Fehlfunktion dieses Signalwegs führt zu massiven Fehlbildungen im Laufe der Embryonalentwicklung und kann bei Erwachsenen Krebs verursachen. In Säugetieren sind zurzeit drei Hedgehog-Proteine bekannt ("sonic hedgehog", "indian hedgehog" und "desert hedgehog").