Ge Xuecai, Milenkovic Ljiljana, Suyama Kaye, Hartl Tom, Purzner Teresa, Winans Amy, Meyer Tobias, Scott Matthew P
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.
Elife. 2015 Sep 15;4:e07068. doi: 10.7554/eLife.07068.
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.
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。