Neuropilin-1 promotes Hedgehog signaling through a novel cytoplasmic motif
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc..
Hedgehog (HH) signaling critically regulates embryonic and postnatal development as well as adult tissue homeostasis, and its perturbation can lead to developmental disorders, birth defects, and cancers. Neuropilins (NRPs), which have well-defined roles in Semaphorin and VEGF signaling, positively regulate HH pathway function, although their mechanism of action in HH signaling remains unclear. Here, using luciferase-based reporter assays, we provide evidence that NRP1 regulates HH signaling specifically at the level of GLI transcriptional activator function. Moreover, we show that NRP1 localization to the primary cilium, a key platform for HH signal transduction, does not correlate with HH signal promotion. Rather, a structure-function analysis suggests that the NRP1 cytoplasmic and transmembrane domains are necessary and sufficient to regulate HH pathway activity. Furthermore, we identify a previously uncharacterized, 12-amino acid region within the NRP1 cytoplasmic domain that mediates HH signal promotion. Overall, our results provide mechanistic insight into NRP1 function within and potentially beyond the HH signaling pathway. These insights have implications for the development of novel modulators of HH-driven developmental disorders and diseases.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:292 |
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| Enthalten in: |
The Journal of biological chemistry - 292(2017), 37 vom: 15. Sept., Seite 15192-15204 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pinskey, Justine M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 27.09.2017 Date Revised 05.02.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1074/jbc.M117.783845 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM273443925 |
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| 520 | |a © 2017 by The American Society for Biochemistry and Molecular Biology, Inc. | ||
| 520 | |a Hedgehog (HH) signaling critically regulates embryonic and postnatal development as well as adult tissue homeostasis, and its perturbation can lead to developmental disorders, birth defects, and cancers. Neuropilins (NRPs), which have well-defined roles in Semaphorin and VEGF signaling, positively regulate HH pathway function, although their mechanism of action in HH signaling remains unclear. Here, using luciferase-based reporter assays, we provide evidence that NRP1 regulates HH signaling specifically at the level of GLI transcriptional activator function. Moreover, we show that NRP1 localization to the primary cilium, a key platform for HH signal transduction, does not correlate with HH signal promotion. Rather, a structure-function analysis suggests that the NRP1 cytoplasmic and transmembrane domains are necessary and sufficient to regulate HH pathway activity. Furthermore, we identify a previously uncharacterized, 12-amino acid region within the NRP1 cytoplasmic domain that mediates HH signal promotion. Overall, our results provide mechanistic insight into NRP1 function within and potentially beyond the HH signaling pathway. These insights have implications for the development of novel modulators of HH-driven developmental disorders and diseases | ||
| 650 | 4 | |a Comparative Study | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Hedgehog signaling pathway | |
| 650 | 4 | |a Neuropilin | |
| 650 | 4 | |a PKA | |
| 650 | 4 | |a cell signaling | |
| 650 | 4 | |a cell surface receptor | |
| 650 | 4 | |a cilia | |
| 650 | 4 | |a signal transduction | |
| 650 | 7 | |a GLI2 protein, human |2 NLM | |
| 650 | 7 | |a Hedgehog Proteins |2 NLM | |
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| 700 | 1 | |a Franks, Nicole E |e verfasserin |4 aut | |
| 700 | 1 | |a McMellen, Alexandra N |e verfasserin |4 aut | |
| 700 | 1 | |a Giger, Roman J |e verfasserin |4 aut | |
| 700 | 1 | |a Allen, Benjamin L |e verfasserin |4 aut | |
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