General Information:

Id: 5,868 (click here to show other Interactions for entry)
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: 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 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 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