The Hedgehog proteins were discovered in Drosophila .
At least three genes encode Hedgehog proteins in vertebrates—Sonic, Desert, and Indian hedgehog. The active forms of all Hedgehog proteins are covalently coupled to cholesterol, as well as to a fatty acid chain.
The effects of Hedgehog are mediated by a latent transcription regulator called Cubitus interruptus (Ci).
1.In the absence of a Hedgehog signal- Most Patched is in intracellular vesicles , where it keeps Smoothened inactive and sequestered. The Ci protein is bound in a cytosolic protein degradation complex, which includes the protein kinase Fused and the scaffold protein Costal2. Costal2 recruits three other protein kinases (PKA, GSK3, and CK1; not shown), which phosphorylate Ci. Phosphorylated Ci is ubiquitylated and then cleaved in proteasomes to form a transcriptional repressor, which accumulates in the nucleus to help keep Hedgehog target genes inactive.
2.In the presence of a Hedgehog signal- Binding to iHog and Patched removes the inhibition of Smoothened by Patched. Smoothened is phosphorylated by PKA and CK1 and translocates to the plasma membrane, where it recruits the complex containing Fused, Costal2, and Ci. Costal2 releases unprocessed Ci, which accumulates in the nucleus and activates the transcription of Hedgehog target genes. Many details in the pathway are poorly understood, including the role of Fused.
Hedgehog functions by blocking the proteolytic processing of Ci, thereby changing it into a transcriptional activator. It does this by a convoluted signaling process that depends on three transmembrane proteins:
( Patched, iHog, and Smoothened. )
. Hedgehog signaling can promote cell proliferation, and excessive Hedgehog signaling can lead to cancer. Inactivating mutations in one of the two human Patched genes, for example, which lead to excessive Hedgehog signaling, occur frequently in basal cell carcinoma of the skin, the most common form of cancer in Caucasians. A small molecule called cyclopamine, made by a meadow lily, is being used to treat cancers associated with excessive Hedgehog signaling. It blocks Hedgehog signaling by binding tightly to Smoothened and inhibiting its activity.
At least three genes encode Hedgehog proteins in vertebrates—Sonic, Desert, and Indian hedgehog. The active forms of all Hedgehog proteins are covalently coupled to cholesterol, as well as to a fatty acid chain.
The effects of Hedgehog are mediated by a latent transcription regulator called Cubitus interruptus (Ci).
1.In the absence of a Hedgehog signal- Most Patched is in intracellular vesicles , where it keeps Smoothened inactive and sequestered. The Ci protein is bound in a cytosolic protein degradation complex, which includes the protein kinase Fused and the scaffold protein Costal2. Costal2 recruits three other protein kinases (PKA, GSK3, and CK1; not shown), which phosphorylate Ci. Phosphorylated Ci is ubiquitylated and then cleaved in proteasomes to form a transcriptional repressor, which accumulates in the nucleus to help keep Hedgehog target genes inactive.
2.In the presence of a Hedgehog signal- Binding to iHog and Patched removes the inhibition of Smoothened by Patched. Smoothened is phosphorylated by PKA and CK1 and translocates to the plasma membrane, where it recruits the complex containing Fused, Costal2, and Ci. Costal2 releases unprocessed Ci, which accumulates in the nucleus and activates the transcription of Hedgehog target genes. Many details in the pathway are poorly understood, including the role of Fused.
Hedgehog functions by blocking the proteolytic processing of Ci, thereby changing it into a transcriptional activator. It does this by a convoluted signaling process that depends on three transmembrane proteins:
( Patched, iHog, and Smoothened. )
. Hedgehog signaling can promote cell proliferation, and excessive Hedgehog signaling can lead to cancer. Inactivating mutations in one of the two human Patched genes, for example, which lead to excessive Hedgehog signaling, occur frequently in basal cell carcinoma of the skin, the most common form of cancer in Caucasians. A small molecule called cyclopamine, made by a meadow lily, is being used to treat cancers associated with excessive Hedgehog signaling. It blocks Hedgehog signaling by binding tightly to Smoothened and inhibiting its activity.
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