Suppr超能文献

磷酸二酯酶4D在神经纤毛蛋白下游发挥作用,以控制刺猬信号转导和髓母细胞瘤的生长。

Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma.

作者信息

Ge Xuecai, Milenkovic Ljiljana, Suyama Kaye, Hartl Tom, Purzner Teresa, Winans Amy, Meyer Tobias, Scott Matthew P

机构信息

Department of Developmental Biology, Department of Genetics, Department of Bioengineering, Stanford University School of Medicine, Stanford, United States.

Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States.

出版信息

Elife. 2015 Sep 15;4:e07068. doi: 10.7554/eLife.07068.

Abstract

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.

摘要

刺猬索尼克(Hh)信号通路的改变会导致出生缺陷和癌症,包括髓母细胞瘤,这是最常见的儿童脑肿瘤。尽管靶向膜蛋白平滑受体(Smoothened)的抑制剂可抑制Hh信号通路,但获得性耐药和肿瘤复发促使人们寻找其他治疗靶点。在这里,我们表明磷酸二酯酶4D(PDE4D)在神经纤毛蛋白下游发挥作用,以控制Hh信号转导和髓母细胞瘤生长。PDE4D直接与神经纤毛蛋白相互作用,神经纤毛蛋白是Hh信号通路的正向调节因子。神经纤毛蛋白配体Semaphorin3增强了这种相互作用,促进PDE4D向质膜的转位和cAMP的降解。由此对蛋白激酶A(PKA)的抑制增强了Hh信号转导。在发育中的小脑中,神经纤毛蛋白的基因敲除降低了Hh信号活性,并抑制了颗粒神经元前体细胞的增殖。在小鼠髓母细胞瘤同种异体移植中,PDE4D抑制剂抑制Hh信号转导并抑制肿瘤生长。我们的研究结果揭示了一种新的Hh信号转导调节机制,并突出了PDE4D作为治疗Hh相关肿瘤的一个有前景的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b7e/4569902/2cf318736f63/elife07068f001.jpg

相似文献

2
Neuropilin-2 contributes to tumorigenicity in a mouse model of Hedgehog pathway medulloblastoma.
J Neurooncol. 2013 Nov;115(2):161-8. doi: 10.1007/s11060-013-1216-1. Epub 2013 Sep 12.
3
Neuropilins are positive regulators of Hedgehog signal transduction.
Genes Dev. 2011 Nov 15;25(22):2333-46. doi: 10.1101/gad.173054.111. Epub 2011 Nov 3.
4
Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome.
Mol Biol Cell. 2021 Sep 1;32(19):1807-1817. doi: 10.1091/mbc.E21-02-0064. Epub 2021 Jul 14.
5
Neuropilin-1 promotes Hedgehog signaling through a novel cytoplasmic motif.
J Biol Chem. 2017 Sep 15;292(37):15192-15204. doi: 10.1074/jbc.M117.783845. Epub 2017 Jun 30.
7
Hedgehog signaling drives medulloblastoma growth via CDK6.
J Clin Invest. 2018 Jan 2;128(1):120-124. doi: 10.1172/JCI92710. Epub 2017 Nov 20.
8
Statins Synergize with Hedgehog Pathway Inhibitors for Treatment of Medulloblastoma.
Clin Cancer Res. 2018 Mar 15;24(6):1375-1388. doi: 10.1158/1078-0432.CCR-17-2923. Epub 2018 Feb 6.
9
10

引用本文的文献

1
Hedgehog pathway, cell cycle, and primary cilium.
Cell Death Discov. 2025 Jul 3;11(1):302. doi: 10.1038/s41420-025-02605-7.
2
PDE4D drives rewiring of the MAPK pathway in BRAF-mutated melanoma resistant to MAPK inhibitors.
Cell Commun Signal. 2024 Nov 21;22(1):559. doi: 10.1186/s12964-024-01941-y.
3
Semaphorin Receptors Antagonize Wnt Signaling Through Beta-Catenin Degradation.
bioRxiv. 2024 May 29:2024.05.29.596372. doi: 10.1101/2024.05.29.596372.
4
A Benzarone Derivative Inhibits EYA to Suppress Tumor Growth in SHH Medulloblastoma.
Cancer Res. 2024 Mar 15;84(6):872-886. doi: 10.1158/0008-5472.CAN-22-3784.
5
cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment.
J Hematol Oncol. 2024 Jan 17;17(1):5. doi: 10.1186/s13045-024-01524-x.
6
Hedgehog Signaling in Cortical Development.
Cells. 2023 Dec 21;13(1):21. doi: 10.3390/cells13010021.
7
Plexins promote Hedgehog signaling through their cytoplasmic GAP activity.
Elife. 2022 Sep 28;11:e74750. doi: 10.7554/eLife.74750.
8
Dissection of the microRNA Network Regulating Hedgehog Signaling in .
Front Cell Dev Biol. 2022 Apr 28;10:866491. doi: 10.3389/fcell.2022.866491. eCollection 2022.
9
Control of the Hedgehog pathway by compartmentalized PKA in the primary cilium.
Sci China Life Sci. 2022 Mar;65(3):500-514. doi: 10.1007/s11427-021-1975-9. Epub 2021 Sep 7.
10
Neuropilin-1: A Key Protein to Consider in the Progression of Pediatric Brain Tumors.
Front Oncol. 2021 Jul 1;11:665634. doi: 10.3389/fonc.2021.665634. eCollection 2021.

本文引用的文献

1
An in vivo chemical genetic screen identifies phosphodiesterase 4 as a pharmacological target for hedgehog signaling inhibition.
Cell Rep. 2015 Apr 7;11(1):43-50. doi: 10.1016/j.celrep.2015.03.001. Epub 2015 Mar 26.
2
The Eya1 phosphatase promotes Shh signaling during hindbrain development and oncogenesis.
Dev Cell. 2015 Apr 6;33(1):22-35. doi: 10.1016/j.devcel.2015.01.033. Epub 2015 Mar 26.
3
Cyclic nucleotide-based therapeutics for chronic obstructive pulmonary disease.
Curr Opin Pharmacol. 2014 Jun;16:89-107. doi: 10.1016/j.coph.2014.04.001. Epub 2014 May 6.
4
Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.
Cancer Cell. 2014 Mar 17;25(3):393-405. doi: 10.1016/j.ccr.2014.02.004.
5
Klotho regulates retinal pigment epithelial functions and protects against oxidative stress.
J Neurosci. 2013 Oct 9;33(41):16346-59. doi: 10.1523/JNEUROSCI.0402-13.2013.
6
Neuropilin-2 contributes to tumorigenicity in a mouse model of Hedgehog pathway medulloblastoma.
J Neurooncol. 2013 Nov;115(2):161-8. doi: 10.1007/s11060-013-1216-1. Epub 2013 Sep 12.
7
Interaction of PACAP with Sonic hedgehog reveals complex regulation of the hedgehog pathway by PKA.
Cell Signal. 2013 Nov;25(11):2222-30. doi: 10.1016/j.cellsig.2013.07.012. Epub 2013 Jul 18.
8
The mechanisms of Hedgehog signalling and its roles in development and disease.
Nat Rev Mol Cell Biol. 2013 Jul;14(7):416-29. doi: 10.1038/nrm3598. Epub 2013 May 30.
9
Phosphodiesterase-4 inhibitors: a review of current developments (2010 - 2012).
Expert Opin Ther Pat. 2013 Aug;23(8):997-1016. doi: 10.1517/13543776.2013.794789. Epub 2013 May 4.

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验