Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease
The Hh/GLI signaling pathway was originally discovered in <i>Drosophila</i> 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 signalin...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/14/3410 |
| _version_ | 1797527519989071872 |
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| author | Ashley N. Sigafoos Brooke D. Paradise Martin E. Fernandez-Zapico |
| author_facet | Ashley N. Sigafoos Brooke D. Paradise Martin E. Fernandez-Zapico |
| author_sort | Ashley N. Sigafoos |
| collection | DOAJ |
| description | The Hh/GLI signaling pathway was originally discovered in <i>Drosophila</i> 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. |
| first_indexed | 2024-03-10T09:43:55Z |
| format | Article |
| id | doaj.art-45ac0cbc10a547be9a73851e731d7f9c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T09:43:55Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-45ac0cbc10a547be9a73851e731d7f9c2023-11-22T03:22:41ZengMDPI AGCancers2072-66942021-07-011314341010.3390/cancers13143410Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for DiseaseAshley N. Sigafoos0Brooke D. Paradise1Martin E. Fernandez-Zapico2Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USASchulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USASchulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USAThe Hh/GLI signaling pathway was originally discovered in <i>Drosophila</i> 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.https://www.mdpi.com/2072-6694/13/14/3410hedgehogcancerGLISUFUcanonical and non-canonical activationHh pathway inhibitors |
| spellingShingle | Ashley N. Sigafoos Brooke D. Paradise Martin E. Fernandez-Zapico Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease Cancers hedgehog cancer GLI SUFU canonical and non-canonical activation Hh pathway inhibitors |
| title | Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease |
| title_full | Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease |
| title_fullStr | Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease |
| title_full_unstemmed | Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease |
| title_short | Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease |
| title_sort | hedgehog gli signaling pathway transduction regulation and implications for disease |
| topic | hedgehog cancer GLI SUFU canonical and non-canonical activation Hh pathway inhibitors |
| url | https://www.mdpi.com/2072-6694/13/14/3410 |
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