刺猬信号通路（英语：Hedgehog signaling pathway）是重要的信号传导通路。
果蠅的刺蝟 (hh) 基因被發現為其中一種可以造成個體體節前後差異的重要基因。果蠅的刺蝟基因在1992年分別被 Jym Mohler, Philip Beachy, 以及 Thomas B. Kornberg的實驗室所複製出來。 若其中一些刺蝟基因發生突變，將會造成相較於野生型來說，較為短小且矮胖的不正常形狀胚胎。 The function of the hedgehog segment polarity gene has been studied in terms of its influence on the normally polarized distribution of larval cuticular denticles as well as features on adult appendages such as legs and antennae. Rather than the normal pattern of denticles, hedgehog mutant larvae tend to have "solid lawns" of denticles (Figure 1). The appearance of the stubby and "hairy" larvae inspired the name 'hedgehog'.
昆蟲細胞表現出大量含有鋅指的 轉錄因子 Cubitus interruptus (Ci蛋白), 而此蛋白會在細胞質中和 kinesin- like protein Costal-2 (Cos2) 形成複合體並結合到微管上 (圖 2)。 The SCF complex targets the 155 kDa full length Ci protein for proteosome-dependent cleavage, which generates a 75 kDa fragment (CiR). CiR builds up in the cell and diffuses into the nucleus, where it acts as a co-repressor for Hh target genes. 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 (圖 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.
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.
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- http://hedgehog.sfsu.edu (Hedgehog Pathway Database)
- http://www.novusbio.com/hedgehogpathway.html (Hedgehog Signaling Pathway Diagram)
- Netpath - A curated resource of signal transduction pathways in humans