Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma
Alterations in Hedgehog (Hh) signaling lead to birth defects and cancers including medulloblastoma, the most common pediatric brain tumor. Although inhibitors targeting the membrane protein Smoothened suppress Hh signaling, acquired drug resistance and tumor relapse call for additional therapeutic t...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2015-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/07068 |
| _version_ | 1811200201945251840 |
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| author | Xuecai Ge Ljiljana Milenkovic Kaye Suyama Tom Hartl Teresa Purzner Amy Winans Tobias Meyer Matthew P Scott |
| author_facet | Xuecai Ge Ljiljana Milenkovic Kaye Suyama Tom Hartl Teresa Purzner Amy Winans Tobias Meyer Matthew P Scott |
| author_sort | Xuecai Ge |
| collection | DOAJ |
| description | Alterations in Hedgehog (Hh) signaling lead to birth defects and cancers including medulloblastoma, the most common pediatric brain tumor. Although inhibitors targeting the membrane protein Smoothened suppress Hh signaling, acquired drug resistance and tumor relapse call for additional therapeutic targets. Here we show that phosphodiesterase 4D (PDE4D) acts downstream of Neuropilins to control Hh transduction and medulloblastoma growth. PDE4D interacts directly with Neuropilins, positive regulators of Hh pathway. The Neuropilin ligand Semaphorin3 enhances this interaction, promoting PDE4D translocation to the plasma membrane and cAMP degradation. The consequent inhibition of protein kinase A (PKA) enhances Hh transduction. In the developing cerebellum, genetic removal of Neuropilins reduces Hh signaling activity and suppresses proliferation of granule neuron precursors. In mouse medulloblastoma allografts, PDE4D inhibitors suppress Hh transduction and inhibit tumor growth. Our findings reveal a new regulatory mechanism of Hh transduction, and highlight PDE4D as a promising target to treat Hh-related tumors. |
| first_indexed | 2024-04-12T02:00:47Z |
| format | Article |
| id | doaj.art-d522917cc8f647e091e354e1888482d2 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:00:47Z |
| publishDate | 2015-09-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj.art-d522917cc8f647e091e354e1888482d22022-12-22T03:52:41ZengeLife Sciences Publications LtdeLife2050-084X2015-09-01410.7554/eLife.07068Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastomaXuecai Ge0Ljiljana Milenkovic1Kaye Suyama2Tom Hartl3Teresa Purzner4Amy Winans5Tobias Meyer6Matthew P Scott7Department of Developmental Biology, Department of Genetics, Department of Bioengineering, Stanford University School of Medicine, Stanford, United StatesDepartment of Developmental Biology, Department of Genetics, Department of Bioengineering, Stanford University School of Medicine, Stanford, United StatesDepartment of Developmental Biology, Department of Genetics, Department of Bioengineering, Stanford University School of Medicine, Stanford, United StatesDepartment of Developmental Biology, Department of Genetics, Department of Bioengineering, Stanford University School of Medicine, Stanford, United StatesDepartment of Developmental Biology, Department of Genetics, Department of Bioengineering, Stanford University School of Medicine, Stanford, United StatesDepartment of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United StatesDepartment of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United StatesDepartment of Developmental Biology, Department of Genetics, Department of Bioengineering, Stanford University School of Medicine, Stanford, United StatesAlterations in Hedgehog (Hh) signaling lead to birth defects and cancers including medulloblastoma, the most common pediatric brain tumor. Although inhibitors targeting the membrane protein Smoothened suppress Hh signaling, acquired drug resistance and tumor relapse call for additional therapeutic targets. Here we show that phosphodiesterase 4D (PDE4D) acts downstream of Neuropilins to control Hh transduction and medulloblastoma growth. PDE4D interacts directly with Neuropilins, positive regulators of Hh pathway. The Neuropilin ligand Semaphorin3 enhances this interaction, promoting PDE4D translocation to the plasma membrane and cAMP degradation. The consequent inhibition of protein kinase A (PKA) enhances Hh transduction. In the developing cerebellum, genetic removal of Neuropilins reduces Hh signaling activity and suppresses proliferation of granule neuron precursors. In mouse medulloblastoma allografts, PDE4D inhibitors suppress Hh transduction and inhibit tumor growth. Our findings reveal a new regulatory mechanism of Hh transduction, and highlight PDE4D as a promising target to treat Hh-related tumors.https://elifesciences.org/articles/07068Hedgehog signal transductionSemaphorin 3NeuropilinmedulloblastomaPhosphodiesterase 4Dtumors resistant to Smo-inhibitor |
| spellingShingle | Xuecai Ge Ljiljana Milenkovic Kaye Suyama Tom Hartl Teresa Purzner Amy Winans Tobias Meyer Matthew P Scott Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma eLife Hedgehog signal transduction Semaphorin 3 Neuropilin medulloblastoma Phosphodiesterase 4D tumors resistant to Smo-inhibitor |
| title | Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma |
| title_full | Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma |
| title_fullStr | Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma |
| title_full_unstemmed | Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma |
| title_short | Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma |
| title_sort | phosphodiesterase 4d acts downstream of neuropilin to control hedgehog signal transduction and the growth of medulloblastoma |
| topic | Hedgehog signal transduction Semaphorin 3 Neuropilin medulloblastoma Phosphodiesterase 4D tumors resistant to Smo-inhibitor |
| url | https://elifesciences.org/articles/07068 |
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