Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease

The Hh/GLI signaling pathway was originally discovered in Drosophila as a major regulator of segment patterning in development. This pathway consists of a series of ligands (Shh, Ihh, and Dhh), transmembrane receptors (Ptch1 and Ptch2), transcription factors (GLI1–3), and signaling regulators (SMO,...

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Bibliographic Details
Published in:Cancers 2021-07, Vol.13 (14), p.3410
Main Authors: Sigafoos, Ashley N., Paradise, Brooke D., Fernandez-Zapico, Martin E.
Format: Article
Language:English
Subjects:
Apoptosis
Basal cell carcinoma
Caspase
Cell cycle
Cholesterol
Colorectal carcinoma
Disease
Gene loci
Hedgehog protein
Insects
Ligands
Medulloblastoma
Mutation
Ovaries
Pancreas
Pancreatic carcinoma
Pattern formation
Prostate
Protein kinase A
Proteins
Regulation
Review
Signal transduction
Stem cells
Transcription factors
Tumors
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Summary:The Hh/GLI signaling pathway was originally discovered in Drosophila as a major regulator of segment patterning in development. This pathway consists of a series of ligands (Shh, Ihh, and Dhh), transmembrane receptors (Ptch1 and Ptch2), transcription factors (GLI1–3), and signaling regulators (SMO, HHIP, SUFU, PKA, CK1, GSK3β, etc.) that work in concert to repress (Ptch1, Ptch2, SUFU, PKA, CK1, GSK3β) or activate (Shh, Ihh, Dhh, SMO, GLI1–3) the signaling cascade. Not long after the initial discovery, dysregulation of the Hh/GLI signaling pathway was implicated in human disease. Activation of this signaling pathway is observed in many types of cancer, including basal cell carcinoma, medulloblastoma, colorectal, prostate, pancreatic, and many more. Most often, the activation of the Hh/GLI pathway in cancer occurs through a ligand-independent mechanism. However, in benign disease, this activation is mostly ligand-dependent. The upstream signaling component of the receptor complex, SMO, is bypassed, and the GLI family of transcription factors can be activated regardless of ligand binding. Additional mechanisms of pathway activation exist whereby the entirety of the downstream signaling pathway is bypassed, and PTCH1 promotes cell cycle progression and prevents caspase-mediated apoptosis. Throughout this review, we summarize each component of the signaling cascade, non-canonical modes of pathway activation, and the implications in human disease, including cancer.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13143410