Limits...
Cooperative integration between HEDGEHOG-GLI signalling and other oncogenic pathways: implications for cancer therapy.

Pandolfi S, Stecca B - Expert Rev Mol Med (2015)

Bottom Line: HH-GLI signalling is initiated by binding of HH ligands to the transmembrane receptor PATCHED and is mediated by transcriptional effectors that belong to the GLI family, whose activity is finely tuned by a number of molecular interactions and post-translation modifications.Several reports suggest that the activity of the GLI proteins is regulated by several proliferative and oncogenic inputs, in addition or independent of upstream HH signalling.We then summarise the latest advances on SMO and GLI inhibitors and alternative approaches to attenuate HH signalling through rational combinatorial therapies.

View Article: PubMed Central - PubMed

Affiliation: Core Research Laboratory,Istituto Toscano Tumori,Florence,Italy.

ABSTRACT
The HEDGEHOG-GLI (HH-GLI) signalling is a key pathway critical in embryonic development, stem cell biology and tissue homeostasis. In recent years, aberrant activation of HH-GLI signalling has been linked to several types of cancer, including those of the skin, brain, lungs, prostate, gastrointestinal tract and blood. HH-GLI signalling is initiated by binding of HH ligands to the transmembrane receptor PATCHED and is mediated by transcriptional effectors that belong to the GLI family, whose activity is finely tuned by a number of molecular interactions and post-translation modifications. Several reports suggest that the activity of the GLI proteins is regulated by several proliferative and oncogenic inputs, in addition or independent of upstream HH signalling. The identification of this complex crosstalk and the understanding of how the major oncogenic signalling pathways interact in cancer is a crucial step towards the establishment of efficient targeted combinatorial treatments. Here we review recent findings on the cooperative integration of HH-GLI signalling with the major oncogenic inputs and we discuss how these cues modulate the activity of the GLI proteins in cancer. We then summarise the latest advances on SMO and GLI inhibitors and alternative approaches to attenuate HH signalling through rational combinatorial therapies.

Show MeSH

Related in: MedlinePlus

Key components of the mammalian HH signalling pathway. In absence of HH ligands (a), PTCH inhibits SMO by preventing its entry into the primary cilium. GLI proteins are phosphorylated by PKA, GSK3β and CK1, which create binding sites for the E3 ubiquitin ligase β-TrCP. GLI3 and, to a lesser extent, GLI2 undergo partial proteasome degradation, leading to the formation of repressor forms (GLI3/2R, red), that translocate into the nucleus where they inhibit the transcription of HH target genes. Full-length GLI may also be completely degraded by the proteasome. This process can be mediated by Spop and Cullin 3-based E3 ligase for GLI2 and GLI3, whereas GLI1 can be degraded by β-TrCP, the Numb-activated Itch E3 ubiquitin ligase and by PCAF (see text for details). Upon HH ligand binding (b), PTCH is displaced from the primary cilium, allowing accumulation and activation of SMO. Active SMO promotes a signalling cascade that ultimately leads to translocation of full length (FL) activated forms of GLI (GLIA, green) into the nucleus, where they induce transcription of HH target genes. Abbreviations: CK1, casein kinase 1; GSK3β, glycogen synthase kinase 3β; HH, Hedgehog; PCAF, p300/CREB-binding protein (CBP)-associated factor; PKA, protein kinase A; PTCH, Patched; SMO, Smoothened; Spop, speckle-type POZ protein; SUFU, Suppressor of Fused; β-TrCP, β-transducin repeat-containing protein.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4836208&req=5

fig01: Key components of the mammalian HH signalling pathway. In absence of HH ligands (a), PTCH inhibits SMO by preventing its entry into the primary cilium. GLI proteins are phosphorylated by PKA, GSK3β and CK1, which create binding sites for the E3 ubiquitin ligase β-TrCP. GLI3 and, to a lesser extent, GLI2 undergo partial proteasome degradation, leading to the formation of repressor forms (GLI3/2R, red), that translocate into the nucleus where they inhibit the transcription of HH target genes. Full-length GLI may also be completely degraded by the proteasome. This process can be mediated by Spop and Cullin 3-based E3 ligase for GLI2 and GLI3, whereas GLI1 can be degraded by β-TrCP, the Numb-activated Itch E3 ubiquitin ligase and by PCAF (see text for details). Upon HH ligand binding (b), PTCH is displaced from the primary cilium, allowing accumulation and activation of SMO. Active SMO promotes a signalling cascade that ultimately leads to translocation of full length (FL) activated forms of GLI (GLIA, green) into the nucleus, where they induce transcription of HH target genes. Abbreviations: CK1, casein kinase 1; GSK3β, glycogen synthase kinase 3β; HH, Hedgehog; PCAF, p300/CREB-binding protein (CBP)-associated factor; PKA, protein kinase A; PTCH, Patched; SMO, Smoothened; Spop, speckle-type POZ protein; SUFU, Suppressor of Fused; β-TrCP, β-transducin repeat-containing protein.

Mentions: The initiation of the HH signalling begins with the binding of one of the three HH ligands, each with distinct spatial and temporal expression patterns, to the 12-pass transmembrane protein receptor PTCH, which resides in the primary cilium, a non-motile structure that functions as a sensor and coordinator centre for the HH signalling (Refs 9, 10, 11). Binding of HH ligands to PTCH relieves its inhibitory effect on the G-protein-coupled receptor-like SMO, which moves into the tip of the cilium and triggers a cascade of events that promote the formation of GLI activator forms (GLI-A). GLI2/3-A translocate into the nucleus and induce HH pathway target genes, including GLI1 (Refs 12, 13, 14) (Fig. 1). In absence of HH ligands, PTCH inhibits pathway activation by preventing SMO to enter the cilium. This results in the phosphorylation and proteasome-mediated carboxyl cleavage of GLI3 and, to a lesser extent, of GLI2 to their repressor forms (GLI2/3-R; Refs 15, 16). GLI1 is degraded by the proteasome and is transcriptionally repressed, with consequent silencing of the pathway. GLI1 acts exclusively as an activator, whereas GLI2 and GLI3 display both positive and negative transcriptional functions (Refs 15, 17, 18) (Fig. 1).Figure 1.


Cooperative integration between HEDGEHOG-GLI signalling and other oncogenic pathways: implications for cancer therapy.

Pandolfi S, Stecca B - Expert Rev Mol Med (2015)

Key components of the mammalian HH signalling pathway. In absence of HH ligands (a), PTCH inhibits SMO by preventing its entry into the primary cilium. GLI proteins are phosphorylated by PKA, GSK3β and CK1, which create binding sites for the E3 ubiquitin ligase β-TrCP. GLI3 and, to a lesser extent, GLI2 undergo partial proteasome degradation, leading to the formation of repressor forms (GLI3/2R, red), that translocate into the nucleus where they inhibit the transcription of HH target genes. Full-length GLI may also be completely degraded by the proteasome. This process can be mediated by Spop and Cullin 3-based E3 ligase for GLI2 and GLI3, whereas GLI1 can be degraded by β-TrCP, the Numb-activated Itch E3 ubiquitin ligase and by PCAF (see text for details). Upon HH ligand binding (b), PTCH is displaced from the primary cilium, allowing accumulation and activation of SMO. Active SMO promotes a signalling cascade that ultimately leads to translocation of full length (FL) activated forms of GLI (GLIA, green) into the nucleus, where they induce transcription of HH target genes. Abbreviations: CK1, casein kinase 1; GSK3β, glycogen synthase kinase 3β; HH, Hedgehog; PCAF, p300/CREB-binding protein (CBP)-associated factor; PKA, protein kinase A; PTCH, Patched; SMO, Smoothened; Spop, speckle-type POZ protein; SUFU, Suppressor of Fused; β-TrCP, β-transducin repeat-containing protein.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836208&req=5

fig01: Key components of the mammalian HH signalling pathway. In absence of HH ligands (a), PTCH inhibits SMO by preventing its entry into the primary cilium. GLI proteins are phosphorylated by PKA, GSK3β and CK1, which create binding sites for the E3 ubiquitin ligase β-TrCP. GLI3 and, to a lesser extent, GLI2 undergo partial proteasome degradation, leading to the formation of repressor forms (GLI3/2R, red), that translocate into the nucleus where they inhibit the transcription of HH target genes. Full-length GLI may also be completely degraded by the proteasome. This process can be mediated by Spop and Cullin 3-based E3 ligase for GLI2 and GLI3, whereas GLI1 can be degraded by β-TrCP, the Numb-activated Itch E3 ubiquitin ligase and by PCAF (see text for details). Upon HH ligand binding (b), PTCH is displaced from the primary cilium, allowing accumulation and activation of SMO. Active SMO promotes a signalling cascade that ultimately leads to translocation of full length (FL) activated forms of GLI (GLIA, green) into the nucleus, where they induce transcription of HH target genes. Abbreviations: CK1, casein kinase 1; GSK3β, glycogen synthase kinase 3β; HH, Hedgehog; PCAF, p300/CREB-binding protein (CBP)-associated factor; PKA, protein kinase A; PTCH, Patched; SMO, Smoothened; Spop, speckle-type POZ protein; SUFU, Suppressor of Fused; β-TrCP, β-transducin repeat-containing protein.
Mentions: The initiation of the HH signalling begins with the binding of one of the three HH ligands, each with distinct spatial and temporal expression patterns, to the 12-pass transmembrane protein receptor PTCH, which resides in the primary cilium, a non-motile structure that functions as a sensor and coordinator centre for the HH signalling (Refs 9, 10, 11). Binding of HH ligands to PTCH relieves its inhibitory effect on the G-protein-coupled receptor-like SMO, which moves into the tip of the cilium and triggers a cascade of events that promote the formation of GLI activator forms (GLI-A). GLI2/3-A translocate into the nucleus and induce HH pathway target genes, including GLI1 (Refs 12, 13, 14) (Fig. 1). In absence of HH ligands, PTCH inhibits pathway activation by preventing SMO to enter the cilium. This results in the phosphorylation and proteasome-mediated carboxyl cleavage of GLI3 and, to a lesser extent, of GLI2 to their repressor forms (GLI2/3-R; Refs 15, 16). GLI1 is degraded by the proteasome and is transcriptionally repressed, with consequent silencing of the pathway. GLI1 acts exclusively as an activator, whereas GLI2 and GLI3 display both positive and negative transcriptional functions (Refs 15, 17, 18) (Fig. 1).Figure 1.

Bottom Line: HH-GLI signalling is initiated by binding of HH ligands to the transmembrane receptor PATCHED and is mediated by transcriptional effectors that belong to the GLI family, whose activity is finely tuned by a number of molecular interactions and post-translation modifications.Several reports suggest that the activity of the GLI proteins is regulated by several proliferative and oncogenic inputs, in addition or independent of upstream HH signalling.We then summarise the latest advances on SMO and GLI inhibitors and alternative approaches to attenuate HH signalling through rational combinatorial therapies.

View Article: PubMed Central - PubMed

Affiliation: Core Research Laboratory,Istituto Toscano Tumori,Florence,Italy.

ABSTRACT
The HEDGEHOG-GLI (HH-GLI) signalling is a key pathway critical in embryonic development, stem cell biology and tissue homeostasis. In recent years, aberrant activation of HH-GLI signalling has been linked to several types of cancer, including those of the skin, brain, lungs, prostate, gastrointestinal tract and blood. HH-GLI signalling is initiated by binding of HH ligands to the transmembrane receptor PATCHED and is mediated by transcriptional effectors that belong to the GLI family, whose activity is finely tuned by a number of molecular interactions and post-translation modifications. Several reports suggest that the activity of the GLI proteins is regulated by several proliferative and oncogenic inputs, in addition or independent of upstream HH signalling. The identification of this complex crosstalk and the understanding of how the major oncogenic signalling pathways interact in cancer is a crucial step towards the establishment of efficient targeted combinatorial treatments. Here we review recent findings on the cooperative integration of HH-GLI signalling with the major oncogenic inputs and we discuss how these cues modulate the activity of the GLI proteins in cancer. We then summarise the latest advances on SMO and GLI inhibitors and alternative approaches to attenuate HH signalling through rational combinatorial therapies.

Show MeSH
Related in: MedlinePlus