Sonic Hedgehog: Difference between revisions

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= Introduction =

Sonic hedgehog (Shh) is a member of the Hedgehog (Hh) family of secreted extracellular signaling proteins, which serve important roles in regulating both short-range and long-range patterning processes in developing invertebrate and vertebrate tissues<ref>PMID: 7867057</ref>. First discovered in ''Drosophila'', where mutations of the single ''Hedgehog'' gene produces larvae that are covered in hedgehog-like denticles, Hh proteins are encoded by at least three genes in mammals - ''Sonic'', ''Desert'', and ''Indian hedgehog''<ref>PMID: 7916661</ref>. With the ability to control such fundamental processes as the anterioposterior patterning of vertebrate limb buds<ref>PMID: 8269518</ref>, the formation of motor neurons in the neural tube <ref>PMID: 7736596</ref>, and the development and maintenance of tissues and organs<ref>PMID: 10980429</ref>, Shh is the most well-studied member of the Hh signaling proteins<ref name="papinsky">PMID: 10753901</ref>. Excessive signaling in adult cells has been implicated in the development of several human cancers<ref>PMID: 14737121</ref><ref name="Path">PMID: 12044012</ref>.

Sonic hedgehog (Shh) is a member of the Hedgehog (Hh) family of secreted extracellular signaling proteins, which serve important roles in regulating both short-range and long-range patterning processes in developing invertebrate and vertebrate tissues<ref>PMID: 7867057</ref>. First discovered in ''Drosophila'', where mutations of the single ''Hedgehog'' gene produces larvae that are covered in hedgehog-like denticles, Hh proteins are encoded by at least three genes in mammals - ''Sonic'', ''Desert'', and ''Indian hedgehog''<ref>PMID: 7916661</ref>. With the ability to control such fundamental processes as the anterioposterior patterning of vertebrate limb buds<ref>PMID: 8269518</ref>, the formation of motor neurons in the neural tube <ref name="neuron">PMID: 7736596</ref>, and the development and maintenance of tissues and organs<ref>PMID: 10980429</ref>, Shh is the most well-studied member of the Hh signaling proteins<ref name="papinsky">PMID: 10753901</ref>. Excessive signaling in adult cells has been implicated in the development of several human cancers<ref>PMID: 14737121</ref><ref name="Path">PMID: 12044012</ref>.

= Biosynthesis =

Line 18:

= Function =

[[Image: Short and Long-Range.jpg | thumb | '''Figure 2.''' Shh-N is released from the cell membrane for long-range signaling by zinc-dependent proteolysis <ref name="signal"/>. ]]The tetrahedrally coordinated zinc ion of Shh-N, along with the non-coordinating residues thought to assist hydrolysis, are highly conserved among vertebrate Hh proteins. A potential hydrolytic activity is therefore expected to play an important cellular role. In pursuit of a substrate for Shh-N, it was found that <scene name='Sandbox_191/Scene3/6'>Ala 194 and Lys 195</scene> near the C-terminus of one Shh-N molecule can hydrogen bond with residues in the zinc binding site of a second Shh-N molecule. This indicates that the protein may be capable of cleaving between Lys 195 and Ser 196 within its own C-terminus <ref name="Palm"/>. This is the most highly conserved region of Hh proteins<ref name="signal">PMID: 8807822</ref>. The suspected autoproteolytic function of Shh-N has been suggested to liberate the tethered protein from the cell membrane to facilitate long-range signaling <ref name="Palm"/>. However, other possible substrates for Shh-N are also likely, including an Shh receptor or other types of signaling molecules involved in the Shh pathway. Whichever the substrate, the discovery of a potential proteolytic activity for Shh-N seems to provide a mechanism for regulating short-range and long-range signaling, which until now has been poorly understood<ref name="papinsky"/>. Short-range signaling occurs in a contact-dependent fashion and is associated with induction of the floor plate within the neural tube. During long-range signaling, Shh-N acts as a ~~morphonen~~ to establish somite patterning, motor neuron formation in the neural tube, and anteroposterior limb patterning.

[[Image: Short and Long-Range.jpg | thumb | '''Figure 2.''' Shh-N is released from the cell membrane for long-range signaling by zinc-dependent proteolysis <ref name="signal"/>. ]]The tetrahedrally coordinated zinc ion of Shh-N, along with the non-coordinating residues thought to assist hydrolysis, are highly conserved among vertebrate Hh proteins. A potential hydrolytic activity is therefore expected to play an important cellular role. In pursuit of a substrate for Shh-N, it was found that <scene name='Sandbox_191/Scene3/6'>Ala 194 and Lys 195</scene> near the C-terminus of one Shh-N molecule can hydrogen bond with residues in the zinc binding site of a second Shh-N molecule. This indicates that the protein may be capable of cleaving between Lys 195 and Ser 196 within its own C-terminus <ref name="Palm"/>. This is the most highly conserved region of Hh proteins<ref name="signal">PMID: 8807822</ref>. The suspected autoproteolytic function of Shh-N has been suggested to liberate the tethered protein from the cell membrane to facilitate long-range signaling <ref name="Palm"/>. However, other possible substrates for Shh-N are also likely, including an Shh receptor or other types of signaling molecules involved in the Shh pathway. Whichever the substrate, the discovery of a potential proteolytic activity for Shh-N seems to provide a mechanism for regulating short-range and long-range signaling, which until now has been poorly understood<ref name="papinsky"/>. Short-range signaling occurs in a contact-dependent fashion and is associated with induction of the floor plate within the neural tube. During long-range signaling, Shh-N acts as a morphogen to establish somite patterning, motor neuron formation in the neural tube<ref name="neuron"/>, and anteroposterior limb patterning.

== Sonic Signaling: The Shh-Gli Pathway ==

Sonic Hedgehog: Difference between revisions

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@@ Line 5: / Line 5: @@
 = Introduction =
-Sonic hedgehog (Shh) is a member of the Hedgehog (Hh) family of secreted extracellular signaling proteins, which serve important roles in regulating both short-range and long-range patterning processes in developing invertebrate and vertebrate tissues<ref>PMID: 7867057</ref>. First discovered in ''Drosophila'', where mutations of the single ''Hedgehog'' gene produces larvae that are covered in hedgehog-like denticles, Hh proteins are encoded by at least three genes in mammals - ''Sonic'', ''Desert'', and ''Indian hedgehog''<ref>PMID: 7916661</ref>. With the ability to control such fundamental processes as the anterioposterior patterning of vertebrate limb buds<ref>PMID: 8269518</ref>, the formation of motor neurons in the neural tube <ref>PMID: 7736596</ref>, and the development and maintenance of tissues and organs<ref>PMID: 10980429</ref>, Shh is the most well-studied member of the Hh signaling proteins<ref name="papinsky">PMID: 10753901</ref>. Excessive signaling in adult cells has been implicated in the development of several human cancers<ref>PMID: 14737121</ref><ref name="Path">PMID: 12044012</ref>.
+Sonic hedgehog (Shh) is a member of the Hedgehog (Hh) family of secreted extracellular signaling proteins, which serve important roles in regulating both short-range and long-range patterning processes in developing invertebrate and vertebrate tissues<ref>PMID: 7867057</ref>. First discovered in ''Drosophila'', where mutations of the single ''Hedgehog'' gene produces larvae that are covered in hedgehog-like denticles, Hh proteins are encoded by at least three genes in mammals - ''Sonic'', ''Desert'', and ''Indian hedgehog''<ref>PMID: 7916661</ref>. With the ability to control such fundamental processes as the anterioposterior patterning of vertebrate limb buds<ref>PMID: 8269518</ref>, the formation of motor neurons in the neural tube <ref name="neuron">PMID: 7736596</ref>, and the development and maintenance of tissues and organs<ref>PMID: 10980429</ref>, Shh is the most well-studied member of the Hh signaling proteins<ref name="papinsky">PMID: 10753901</ref>. Excessive signaling in adult cells has been implicated in the development of several human cancers<ref>PMID: 14737121</ref><ref name="Path">PMID: 12044012</ref>.
 = Biosynthesis =
@@ Line 18: / Line 18: @@
 = Function =
-[[Image: Short and Long-Range.jpg | thumb | '''Figure 2.''' Shh-N is released from the cell membrane for long-range signaling by zinc-dependent proteolysis <ref name="signal"/>. ]]The tetrahedrally coordinated zinc ion of Shh-N, along with the non-coordinating residues thought to assist hydrolysis, are highly conserved among vertebrate Hh proteins. A potential hydrolytic activity is therefore expected to play an important cellular role. In pursuit of a substrate for Shh-N, it was found that <scene name='Sandbox_191/Scene3/6'>Ala 194 and Lys 195</scene> near the C-terminus of one Shh-N molecule can hydrogen bond with residues in the zinc binding site of a second Shh-N molecule. This indicates that the protein may be capable of cleaving between Lys 195 and Ser 196 within its own C-terminus <ref name="Palm"/>. This is the most highly conserved region of Hh proteins<ref name="signal">PMID: 8807822</ref>. The suspected autoproteolytic function of Shh-N has been suggested to liberate the tethered protein from the cell membrane to facilitate long-range signaling <ref name="Palm"/>. However, other possible substrates for Shh-N are also likely, including an Shh receptor or other types of signaling molecules involved in the Shh pathway. Whichever the substrate, the discovery of a potential proteolytic activity for Shh-N seems to provide a mechanism for regulating short-range and long-range signaling, which until now has been poorly understood<ref name="papinsky"/>. Short-range signaling occurs in a contact-dependent fashion and is associated with induction of the floor plate within the neural tube. During long-range signaling, Shh-N acts as a morphonen to establish somite patterning, motor neuron formation in the neural tube, and anteroposterior limb patterning.
+[[Image: Short and Long-Range.jpg | thumb | '''Figure 2.''' Shh-N is released from the cell membrane for long-range signaling by zinc-dependent proteolysis <ref name="signal"/>. ]]The tetrahedrally coordinated zinc ion of Shh-N, along with the non-coordinating residues thought to assist hydrolysis, are highly conserved among vertebrate Hh proteins. A potential hydrolytic activity is therefore expected to play an important cellular role. In pursuit of a substrate for Shh-N, it was found that <scene name='Sandbox_191/Scene3/6'>Ala 194 and Lys 195</scene> near the C-terminus of one Shh-N molecule can hydrogen bond with residues in the zinc binding site of a second Shh-N molecule. This indicates that the protein may be capable of cleaving between Lys 195 and Ser 196 within its own C-terminus <ref name="Palm"/>. This is the most highly conserved region of Hh proteins<ref name="signal">PMID: 8807822</ref>. The suspected autoproteolytic function of Shh-N has been suggested to liberate the tethered protein from the cell membrane to facilitate long-range signaling <ref name="Palm"/>. However, other possible substrates for Shh-N are also likely, including an Shh receptor or other types of signaling molecules involved in the Shh pathway. Whichever the substrate, the discovery of a potential proteolytic activity for Shh-N seems to provide a mechanism for regulating short-range and long-range signaling, which until now has been poorly understood<ref name="papinsky"/>. Short-range signaling occurs in a contact-dependent fashion and is associated with induction of the floor plate within the neural tube. During long-range signaling, Shh-N acts as a morphogen to establish somite patterning, motor neuron formation in the neural tube<ref name="neuron"/>, and anteroposterior limb patterning.
 == Sonic Signaling: The Shh-Gli Pathway ==