Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome.
Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome.
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Myomegalin通过控制中心体PDE4D调控Hedgehog通路。
DOI：
10.1091/mbc.e21-02-0064
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发表时间：
2021-09-01
影响因子：
3.3
通讯作者：
Ge X
中科院分区：
文献类型：
--
作者：
Peng H;Zhang J;Ya A;Ma W;Villa S;Sukenik S;Ge X
刺猬（Hh）信号的突变与出生缺陷和癌症有关，包括髓母细胞瘤（MB），这是最恶性的儿科脑肿瘤之一。目前的Hh抑制剂面临着耐药性和肿瘤复发的挑战，迫切需要对Hh通路调控的新见解。我们先前的研究揭示了PDE 4D如何控制细胞质中cAMP的整体水平以正向调节Hh信号传导;在本研究中，我们发现一种特定的亚型PDE 4D 3通过Myomegalin（Mmg）（一种中心体/高尔基体相关蛋白）与中心体相连。Mmg缺失使PDE 4D 3从中心体移位，导致局部PKA过度活化和Hh信号传导的抑制，使其他PKA相关途径不受影响。在小鼠模型中，Mmg缺失抑制颗粒神经元前体细胞的增殖并阻断MB的生长。我们的研究结果详细说明了Hh通路的一种新的调节机制，并强调了Hh相关癌症的一种令人兴奋的治疗途径，同时减少了副作用。
Mutations in the hedgehog (Hh) signaling are implicated in birth defects and cancers, including medulloblastoma (MB), one of the most malignant pediatric brain tumors. Current Hh inhibitors face the challenge of drug resistance and tumor relapse, urging new insights in the Hh pathway regulation. Our previous study revealed how PDE4D controls global levels of cAMP in the cytoplasm to positively regulate Hh signaling; in the present study, we found that a specific isoform PDE4D3 is tethered to the centrosome by Myomegalin (Mmg), a centrosome/Golgi-associated protein. Mmg loss dislocates PDE4D3 from the centrosome, leading to local PKA overactivation and inhibition of the Hh signaling, leaving other PKA-related pathways unaffected. Mmg loss suppresses the proliferation of granule neuron precursors and blocks the growth of MB in mouse model. Our findings specify a new regulatory mechanism of the Hh pathway and highlight an exciting therapeutic avenue for Hh-related cancers with reduced side effects.