General Information:

Id: 5,868
Diseases: Diabetes mellitus, type II - [OMIM]
Insulin resistance
Mammalia
review
Reference: Teperino R et al.(2014) Canonical and non-canonical Hedgehog signalling and the control of metabolism Semin. Cell Dev. Biol. 33: 81-92 [PMID: 24862854]

Interaction Information:

Comment Loss of Hedgehog function in the fly results in a disorganized lawn of spiky processes and denticles on the surface of the fly larva, a Hedgehog-like phenotype that coined the name of the pathway. The primary cilium, commonly thought to be a prerogative of Hedgehog signalling in vertebrates, has also been shown to play a central role in flies. Vertebrate canonical Hedgehog signalling is initiated by binding of proteolytically processed and lipid modified Hedgehog ligand to its receptor Patched (Ptch), a twelve-pass transmembrane protein that represses the pathway in the absence of ligand. Three distinct co-receptors, Cdo, Boc, and Gas1, facilitate high-affinity binding of mature Hedgehog ligand to Ptch, thereby enhancing Hedgehog signal strength.
Formal Description
Interaction-ID: 55446

gene/protein

SHH

increases_activity of

in primary cilium
Comment Loss of Hedgehog function in the fly results in a disorganized lawn of spiky processes and denticles on the surface of the fly larva, a Hedgehog-like phenotype that coined the name of the pathway. The primary cilium, commonly thought to be a prerogative of Hedgehog signalling in vertebrates, has also been shown to play a central role in flies. Vertebrate canonical Hedgehog signalling is initiated by binding of proteolytically processed and lipid modified Hedgehog ligand to its receptor Patched (Ptch), a twelve-pass transmembrane protein that represses the pathway in the absence of ligand. Three distinct co-receptors, Cdo, Boc, and Gas1, facilitate high-affinity binding of mature Hedgehog ligand to Ptch, thereby enhancing Hedgehog signal strength.
Formal Description
Interaction-ID: 55448

gene/protein

SHH

interacts (colocalizes) with

gene/protein

PTCH1

in primary cilium
Comment Loss of Hedgehog function in the fly results in a disorganized lawn of spiky processes and denticles on the surface of the fly larva, a Hedgehog-like phenotype that coined the name of the pathway. The primary cilium, commonly thought to be a prerogative of Hedgehog signalling in vertebrates, has also been shown to play a central role in flies. Vertebrate canonical Hedgehog signalling is initiated by binding of proteolytically processed and lipid modified Hedgehog ligand to its receptor Patched (Ptch), a twelve-pass transmembrane protein that represses the pathway in the absence of ligand. Three distinct co-receptors, Cdo, Boc, and Gas1, facilitate high-affinity binding of mature Hedgehog ligand to Ptch, thereby enhancing Hedgehog signal strength.
Formal Description
Interaction-ID: 55449

gene/protein

PTCH1

decreases_activity of

in primary cilium; in the absence of SHH
Comment Loss of Hedgehog function in the fly results in a disorganized lawn of spiky processes and denticles on the surface of the fly larva, a Hedgehog-like phenotype that coined the name of the pathway. The primary cilium, commonly thought to be a prerogative of Hedgehog signalling in vertebrates, has also been shown to play a central role in flies. Vertebrate canonical Hedgehog signalling is initiated by binding of proteolytically processed and lipid modified Hedgehog ligand to its receptor Patched (Ptch), a twelve-pass transmembrane protein that represses the pathway in the absence of ligand. Three distinct co-receptors, Cdo, Boc, and Gas1, facilitate high-affinity binding of mature Hedgehog ligand to Ptch, thereby enhancing Hedgehog signal strength.
Formal Description
Interaction-ID: 55450

gene/protein

CDON

increases_activity of

in primary cilium; via increased binding of SHH to PTCH1
Comment Loss of Hedgehog function in the fly results in a disorganized lawn of spiky processes and denticles on the surface of the fly larva, a Hedgehog-like phenotype that coined the name of the pathway. The primary cilium, commonly thought to be a prerogative of Hedgehog signalling in vertebrates, has also been shown to play a central role in flies. Vertebrate canonical Hedgehog signalling is initiated by binding of proteolytically processed and lipid modified Hedgehog ligand to its receptor Patched (Ptch), a twelve-pass transmembrane protein that represses the pathway in the absence of ligand. Three distinct co-receptors, Cdo, Boc, and Gas1, facilitate high-affinity binding of mature Hedgehog ligand to Ptch, thereby enhancing Hedgehog signal strength.
Formal Description
Interaction-ID: 55451

gene/protein

BOC

increases_activity of

in primary cilium; via increased binding of SHH to PTCH1
Comment Loss of Hedgehog function in the fly results in a disorganized lawn of spiky processes and denticles on the surface of the fly larva, a Hedgehog-like phenotype that coined the name of the pathway. The primary cilium, commonly thought to be a prerogative of Hedgehog signalling in vertebrates, has also been shown to play a central role in flies. Vertebrate canonical Hedgehog signalling is initiated by binding of proteolytically processed and lipid modified Hedgehog ligand to its receptor Patched (Ptch), a twelve-pass transmembrane protein that represses the pathway in the absence of ligand. Three distinct co-receptors, Cdo, Boc, and Gas1, facilitate high-affinity binding of mature Hedgehog ligand to Ptch, thereby enhancing Hedgehog signal strength.
Formal Description
Interaction-ID: 55452

gene/protein

GAS1

increases_activity of

in primary cilium; via increased binding of SHH to PTCH1
Comment Ligand binding to Ptch abrogates its repressive effect on the seven-pass transmembrane protein Smo, a key effector essential for canonical Hedgehog signal transduction. The repressive role of ligand-free Ptch depends on its localization in the primary cilium, a single antenna-like structure that protrudes from the cell surface of most adherent cell types and functions as an organizer-like signal transduction compartment. Ciliary Ptch prevents pathway activation by blocking the entry of Smo into the primary cilium.
Formal Description
Interaction-ID: 55454

gene/protein

PTCH1

decreases_activity of

gene/protein

SMO

in primary cilium; in the absence of SHH
Drugbank entries Show/Hide entries for SMO
Comment Binding of Hedgehog protein to Ptch removes Ptch from the primary cilium, thereby allowing Smo to enter and, upon an unknown activation step, propagate the Hedgehog signal further downstream. Despite intense efforts to understand Ptch function, the detailed mechanisms of how Ptch represses Smo in the absence of ligand is still elusive. Ptch contains a sterol-sensing domain and belongs to the family of RND (Resistance-Nodulation-cell Division) transporters. Several functional studies support a model where Ptch prevents Smo activation either by removing Smo agonists such as oxysterols from the primary cilium or by increasing the influx of Smo antagonists into the cilium. Ptch may also modify the lipid composition of Smo-containing endosomes and therefore negatively control Smo trafficking towards the primary cilium.
Formal Description
Interaction-ID: 55455

gene/protein

SHH

decreases_quantity of

gene/protein

PTCH1

in primary cilium
Comment Binding of Hedgehog protein to Ptch removes Ptch from the primary cilium, thereby allowing Smo to enter and, upon an unknown activation step, propagate the Hedgehog signal further downstream. Despite intense efforts to understand Ptch function, the detailed mechanisms of how Ptch represses Smo in the absence of ligand is still elusive. Ptch contains a sterol-sensing domain and belongs to the family of RND (Resistance-Nodulation-cell Division) transporters. Several functional studies support a model where Ptch prevents Smo activation either by removing Smo agonists such as oxysterols from the primary cilium or by increasing the influx of Smo antagonists into the cilium. Ptch may also modify the lipid composition of Smo-containing endosomes and therefore negatively control Smo trafficking towards the primary cilium.
Formal Description
Interaction-ID: 55456

gene/protein

SHH

increases_quantity of

gene/protein

SMO

in primary cilium
Drugbank entries Show/Hide entries for SMO
Comment The key role of Smo in canonical Hedgehog signalling is to control the activation of the Gli zinc finger transcription factors. Of note, the Gli family member Gli3, and to some extent also Gli2, exerts a dual function as transcriptional repressor (GliR) and activator (GliA) of Hedgehog target genes, where the two distinct functional states are controlled by proteolytic processing. In the off-state of the Hedgehog pathway, Gli3 protein appears to continuously cycle through the primary cilium, where it is proteolytically cleaved into a C-terminally truncated repressor form lacking the transactivation domain. Gli3 repressor protein translocates to the nucleus, where it binds to the promoters of Hedgehog target genes to shut off transcription. The balance between Gli3 repressor and activator is tightly regulated by sequential phosphorylation and dephosphorylation events. Kinases involved are PKA; Gsk-3beta; and Ck1. The detailed mechanisms of how Smo activation in the primary cilium results in Gli activator formation are still unclear.
Formal Description
Interaction-ID: 55457

gene/protein

SMO

increases_activity of

gene/protein

GLI3A

in primary cilium
Drugbank entries Show/Hide entries for SMO
Comment The key role of Smo in canonical Hedgehog signalling is to control the activation of the Gli zinc finger transcription factors. Of note, the Gli family member Gli3, and to some extent also Gli2, exerts a dual function as transcriptional repressor (GliR) and activator (GliA) of Hedgehog target genes, where the two distinct functional states are controlled by proteolytic processing. In the off-state of the Hedgehog pathway, Gli3 protein appears to continuously cycle through the primary cilium, where it is proteolytically cleaved into a C-terminally truncated repressor form lacking the transactivation domain. Gli3 repressor protein translocates to the nucleus, where it binds to the promoters of Hedgehog target genes to shut off transcription. The balance between Gli3 repressor and activator is tightly regulated by sequential phosphorylation and dephosphorylation events. Kinases involved are PKA; Gsk-3beta; and Ck1. The detailed mechanisms of how Smo activation in the primary cilium results in Gli activator formation are still unclear.
Formal Description
Interaction-ID: 55460

gene/protein

SMO

increases_activity of

gene/protein

GLI2

in primary cilium
Drugbank entries Show/Hide entries for SMO
Comment The key role of Smo in canonical Hedgehog signalling is to control the activation of the Gli zinc finger transcription factors. Of note, the Gli family member Gli3, and to some extent also Gli2, exerts a dual function as transcriptional repressor (GliR) and activator (GliA) of Hedgehog target genes, where the two distinct functional states are controlled by proteolytic processing. In the off-state of the Hedgehog pathway, Gli3 protein appears to continuously cycle through the primary cilium, where it is proteolytically cleaved into a C-terminally truncated repressor form lacking the transactivation domain. Gli3 repressor protein translocates to the nucleus, where it binds to the promoters of Hedgehog target genes to shut off transcription. The balance between Gli3 repressor and activator is tightly regulated by sequential phosphorylation and dephosphorylation events. Kinases involved are PKA; Gsk-3beta; and Ck1. The detailed mechanisms of how Smo activation in the primary cilium results in Gli activator formation are still unclear.
Formal Description
Interaction-ID: 55461

gene/protein

PTCH1

increases_activity of

gene/protein

GLI3R

in primary cilium, in nucleus; in the absence of SMO
Comment The key role of Smo in canonical Hedgehog signalling is to control the activation of the Gli zinc finger transcription factors. Of note, the Gli family member Gli3, and to some extent also Gli2, exerts a dual function as transcriptional repressor (GliR) and activator (GliA) of Hedgehog target genes, where the two distinct functional states are controlled by proteolytic processing. In the off-state of the Hedgehog pathway, Gli3 protein appears to continuously cycle through the primary cilium, where it is proteolytically cleaved into a C-terminally truncated repressor form lacking the transactivation domain. Gli3 repressor protein translocates to the nucleus, where it binds to the promoters of Hedgehog target genes to shut off transcription. The balance between Gli3 repressor and activator is tightly regulated by sequential phosphorylation and dephosphorylation events. Kinases involved are PKA; Gsk-3beta; and Ck1. The detailed mechanisms of how Smo activation in the primary cilium results in Gli activator formation are still unclear.
Formal Description
Interaction-ID: 55463

gene/protein

GLI3R

is localized in

cellular component

nucleus

Comment The key role of Smo in canonical Hedgehog signalling is to control the activation of the Gli zinc finger transcription factors. Of note, the Gli family member Gli3, and to some extent also Gli2, exerts a dual function as transcriptional repressor (GliR) and activator (GliA) of Hedgehog target genes, where the two distinct functional states are controlled by proteolytic processing. In the off-state of the Hedgehog pathway, Gli3 protein appears to continuously cycle through the primary cilium, where it is proteolytically cleaved into a C-terminally truncated repressor form lacking the transactivation domain. Gli3 repressor protein translocates to the nucleus, where it binds to the promoters of Hedgehog target genes to shut off transcription. The balance between Gli3 repressor and activator is tightly regulated by sequential phosphorylation and dephosphorylation events. Kinases involved are PKA; Gsk-3beta; and Ck1. The detailed mechanisms of how Smo activation in the primary cilium results in Gli activator formation are still unclear.
Formal Description
Interaction-ID: 55465

complex/PPI

Protein kinase A

affects_activity of

gene/protein

GLI3

Comment The key role of Smo in canonical Hedgehog signalling is to control the activation of the Gli zinc finger transcription factors. Of note, the Gli family member Gli3, and to some extent also Gli2, exerts a dual function as transcriptional repressor (GliR) and activator (GliA) of Hedgehog target genes, where the two distinct functional states are controlled by proteolytic processing. In the off-state of the Hedgehog pathway, Gli3 protein appears to continuously cycle through the primary cilium, where it is proteolytically cleaved into a C-terminally truncated repressor form lacking the transactivation domain. Gli3 repressor protein translocates to the nucleus, where it binds to the promoters of Hedgehog target genes to shut off transcription. The balance between Gli3 repressor and activator is tightly regulated by sequential phosphorylation and dephosphorylation events. Kinases involved are PKA; Gsk-3beta; and Ck1. The detailed mechanisms of how Smo activation in the primary cilium results in Gli activator formation are still unclear.
Formal Description
Interaction-ID: 55470

gene/protein

GSK3B

affects_activity of

gene/protein

GLI3

Drugbank entries Show/Hide entries for GSK3B
Comment The key role of Smo in canonical Hedgehog signalling is to control the activation of the Gli zinc finger transcription factors. Of note, the Gli family member Gli3, and to some extent also Gli2, exerts a dual function as transcriptional repressor (GliR) and activator (GliA) of Hedgehog target genes, where the two distinct functional states are controlled by proteolytic processing. In the off-state of the Hedgehog pathway, Gli3 protein appears to continuously cycle through the primary cilium, where it is proteolytically cleaved into a C-terminally truncated repressor form lacking the transactivation domain. Gli3 repressor protein translocates to the nucleus, where it binds to the promoters of Hedgehog target genes to shut off transcription. The balance between Gli3 repressor and activator is tightly regulated by sequential phosphorylation and dephosphorylation events. Kinases involved are PKA; Gsk-3beta; and Ck1. The detailed mechanisms of how Smo activation in the primary cilium results in Gli activator formation are still unclear.
Formal Description
Interaction-ID: 55471

gene/protein

CSNK1A1

affects_activity of

gene/protein

GLI3

Comment Recent studies suggest that binding of Hedgehog to Ptch removes the ciliary G-protein Coupled Receptor Gpr161. Gpr161 in the cilium inhibits Hedgehog signalling via PKA and Gli3 repressor formation.
Formal Description
Interaction-ID: 55472

gene/protein

SHH

decreases_quantity of

gene/protein

GPR161

in primary cilium; upon binding of SHH to PTCH1
Comment Recent studies suggest that binding of Hedgehog to Ptch removes the ciliary G-protein Coupled Receptor Gpr161. Gpr161 in the cilium inhibits Hedgehog signalling via PKA and Gli3 repressor formation.
Formal Description
Interaction-ID: 55473

gene/protein

GPR161

decreases_activity of

in primary cilium
Comment Recent studies suggest that binding of Hedgehog to Ptch removes the ciliary G-protein Coupled Receptor Gpr161. Gpr161 in the cilium inhibits Hedgehog signalling via PKA and Gli3 repressor formation.
Formal Description
Interaction-ID: 55474

gene/protein

GPR161

increases_activity of

gene/protein

GLI3R

in primary cilium; via PKA
Comment Sufu is a critical negative pathway regulator in vertebrate Hedgehog signalling and prevents nuclear translocation of Gli proteins. As a consequence of Sufu degradation and Gli-Sufu dissociation, Gli activator forms translocate to the nucleus and activate the expression of target genes, which includes a self-amplifying loop via induction of Gli1 itself.
Formal Description
Interaction-ID: 55475

gene/protein

SUFU

decreases_activity of

Comment The Hedgehog signalling pathway is essential for proper embryonic development and thought to be mostly quiescent in adults.
Formal Description
Interaction-ID: 55477

increases_activity of

Comment Inappropriate reactivation of the pathway is associated with disparate human cancers spanning almost every tissue type, including liver, pancreas, brain, stomach and intestine.
Formal Description
Interaction-ID: 55478

affects_activity of

disease

Cancer

Comment Upon liver damage, the secretion of Hedgehog ligands is upregulated in cholangiocytes and myofibroblasts and sustains proliferation and survival in both cell types.
Formal Description
Interaction-ID: 55480

increases_quantity of

tissue/cell line

cholangiocyte

upon liver damage
Comment Upon liver damage, the secretion of Hedgehog ligands is upregulated in cholangiocytes and myofibroblasts and sustains proliferation and survival in both cell types.
Formal Description
Interaction-ID: 55481

increases_quantity of

tissue/cell line

myofibroblast

upon liver damage
Comment In response to damage, hepatic stellate cells (HSCs) undergo an Epithelial-to-Mesenchymal-Transition (EMT) and trans-differentiate into myofibroblasts (MF), resulting in liver fibrosis. Activation of the Hedgehog pathway in HSCs, for example downstream of Leptin signalling, is responsible for HSC to MF trans-differentiation. This cell fate transition is intriguingly dependent upon Gli transcription factors, Hif-1alpha and a metabolic switch towards aerobic glycolysis in HSCs. These findings represent the first evidence of a direct implication of canonical Gli-dependent Hedgehog signalling in glycolytic reprogramming of cellular metabolism. Strikingly, this phenomenon seems to be a common feature of liver damage-induced Hedgehog signalling, as it has been shown in other forms of non-carcinogenic liver damage.
Formal Description
Interaction-ID: 55483

decreases_quantity of

tissue/cell line

hepatic stellate cell

upon liver damage
Comment In response to damage, hepatic stellate cells (HSCs) undergo an Epithelial-to-Mesenchymal-Transition (EMT) and trans-differentiate into myofibroblasts (MF), resulting in liver fibrosis. Activation of the Hedgehog pathway in HSCs, for example downstream of Leptin signalling, is responsible for HSC to MF trans-differentiation. This cell fate transition is intriguingly dependent upon Gli transcription factors, Hif-1alpha and a metabolic switch towards aerobic glycolysis in HSCs. These findings represent the first evidence of a direct implication of canonical Gli-dependent Hedgehog signalling in glycolytic reprogramming of cellular metabolism. Strikingly, this phenomenon seems to be a common feature of liver damage-induced Hedgehog signalling, as it has been shown in other forms of non-carcinogenic liver damage.
Formal Description
Interaction-ID: 55486

increases_activity of

upon liver damage
Comment In response to damage, hepatic stellate cells (HSCs) undergo an Epithelial-to-Mesenchymal-Transition (EMT) and trans-differentiate into myofibroblasts (MF), resulting in liver fibrosis. Activation of the Hedgehog pathway in HSCs, for example downstream of Leptin signalling, is responsible for HSC to MF trans-differentiation. This cell fate transition is intriguingly dependent upon Gli transcription factors, Hif-1alpha and a metabolic switch towards aerobic glycolysis in HSCs. These findings represent the first evidence of a direct implication of canonical Gli-dependent Hedgehog signalling in glycolytic reprogramming of cellular metabolism. Strikingly, this phenomenon seems to be a common feature of liver damage-induced Hedgehog signalling, as it has been shown in other forms of non-carcinogenic liver damage.
Formal Description
Interaction-ID: 55487

increases_activity of

phenotype

liver fibrosis

upon liver damage
Comment In response to damage, hepatic stellate cells (HSCs) undergo an Epithelial-to-Mesenchymal-Transition (EMT) and trans-differentiate into myofibroblasts (MF), resulting in liver fibrosis. Activation of the Hedgehog pathway in HSCs, for example downstream of Leptin signalling, is responsible for HSC to MF trans-differentiation. This cell fate transition is intriguingly dependent upon Gli transcription factors, Hif-1alpha and a metabolic switch towards aerobic glycolysis in HSCs. These findings represent the first evidence of a direct implication of canonical Gli-dependent Hedgehog signalling in glycolytic reprogramming of cellular metabolism. Strikingly, this phenomenon seems to be a common feature of liver damage-induced Hedgehog signalling, as it has been shown in other forms of non-carcinogenic liver damage.
Formal Description
Interaction-ID: 55489

increases_activity of

process

aerobic glycolysis

in hepatic stellate cells; upon liver damage
Comment The hepatocellular carcinoma (HCC) scenario is rather unique. Here, Hedgehog ligands are secreted by malignant hepatocytes, induce Gli-dependent Warburg reprogramming and lactate secretion in stromal cells (mainly myofibroblasts) and lactate signals back to malignant hepatocytes to sustain their growth and survival. This metabolic reprogramming is known as the “Reverse Warburg”. First introduced in 2009, a reverse Warburg effect describes the ability of cancer cells to induce a Warburg effect in neighbouring stromal cells and benefit from the secreted lactate to sustain their proliferation and survival.
Formal Description
Interaction-ID: 55490

increases_activity of

process

reverse Warburg effect

in hepatocellular carcinoma cells
Comment Hedgehog signalling controls development of both endocrine and exocrine pancreas, as well as their function in adults. Furthermore, inappropriate activation of the pathway, alone or in combination with other oncogenes is associated with the development of pancreatic adenocarcinoma (PDAC).
Formal Description
Interaction-ID: 55491

affects_activity of

tissue/cell line

endocrine pancreas

Comment Hedgehog signalling controls development of both endocrine and exocrine pancreas, as well as their function in adults. Furthermore, inappropriate activation of the pathway, alone or in combination with other oncogenes is associated with the development of pancreatic adenocarcinoma (PDAC).
Formal Description
Interaction-ID: 55492

affects_activity of

tissue/cell line

exocrine pancreas

Comment Hedgehog signalling controls development of both endocrine and exocrine pancreas, as well as their function in adults. Furthermore, inappropriate activation of the pathway, alone or in combination with other oncogenes is associated with the development of pancreatic adenocarcinoma (PDAC).
Formal Description
Interaction-ID: 55493

affects_activity of

Comment Canonical Hedgehog signalling controls insulin transcription and secretion.
Formal Description
Interaction-ID: 55494

affects_expression of

gene/protein

INS

Drugbank entries Show/Hide entries for INS
Comment Canonical Hedgehog signalling controls insulin transcription and secretion.
Formal Description
Interaction-ID: 55495

affects_activity of

Comment Hedgehog acts upstream of PPARgamma to channel preadipocytes fate away from adipogenesis towards osteogenesis. This is achieved via Gli-dependent induction of anti-adipogenic transcription factors, with concomitant inhibition of the pro-adipogenic ones. Interestingly, Hedgehog-dependent adipogenesis block is restricted to white adipocyte progenitors. aP2-Sufu knockout mice (which feature constitutive activation of the pathway in both white and brown fat depots) display a white adipose tissue-specific lipoatrophy, with a fully developed and functionally intact brown adipose tissue depot. Thus, Hedgehog was one of the first hormonal axes identified capable of differentially regulating white and brown adipogenesis.
Formal Description
Interaction-ID: 55498

decreases_activity of

in white adipose tissue