Extracellular domain shedding of the ALK receptor mediates neuroblastoma cell migration.
Extracellular domain shedding of the ALK receptor mediates neuroblastoma cell migration.
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DOI：
10.1016/j.celrep.2021.109363
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发表时间：
2021-07-13
期刊：
影响因子：
8.8
通讯作者：
George RE
中科院分区：
文献类型：
--
作者：
Huang H;Gont A;Kee L;Dries R;Pfeifer K;Sharma B;Debruyne DN;Harlow M;Sengupta S;Guan J;Yeung CM;Wang W;Hallberg B;Palmer RH;Irwin MS;George RE
虽然间变性淋巴瘤激酶（ALK）膜受体的激活突变发生在约10%的神经母细胞瘤（NB）肿瘤中，但在大多数非突变病例中异常表达的野生型（WT）受体的作用尚不清楚。WT和突变蛋白都经历细胞外结构域（ECD）切割。在这里，我们将切割位点定位在Asn654-Leu655上，并证明了WT ALK的切割抑制显著阻碍了NB细胞的迁移，从而延长了小鼠模型中的存活时间。切割抑制导致上皮-间质转化（EMT）基因信号下调，减少EMT基因启动子的核定位和β-catenin的占用。我们进一步表明，切割是由基质金属蛋白酶9介导的，其遗传和药理学失活可抑制切割并减少NB细胞的迁移。总之，我们的研究结果表明，WT ALK ECD切割在NB发病机制中起着关键作用，这可能会对治疗有益。Huang等人表明，ALK细胞表面酪氨酸激酶受体的细胞外结构域（ECD）切割通过诱导EMT表型介导神经母细胞瘤细胞迁移。ECD切割是由MMP-9引起的，其抑制导致细胞迁移减少。
Although activating mutations of the anaplastic lymphoma kinase (ALK) membrane receptor occur in ~10% of neuroblastoma (NB) tumors, the role of the wild-type (WT) receptor, which is aberrantly expressed in most non-mutated cases, is unclear. Both WT and mutant proteins undergo extracellular domain (ECD) cleavage. Here, we map the cleavage site to Asn654-Leu655 and demonstrate that cleavage inhibition of WT ALK significantly impedes NB cell migration with subsequent prolongation of survival in mouse models. Cleavage inhibition results in the downregulation of an epithelial-to-mesenchymal transition (EMT) gene signature, with decreased nuclear localization and occupancy of β-catenin at EMT gene promoters. We further show that cleavage is mediated by matrix metalloproteinase 9, whose genetic and pharmacologic inactivation inhibits cleavage and decreases NB cell migration. Together, our results indicate a pivotal role for WT ALK ECD cleavage in NB pathogenesis, which may be harnessed for therapeutic benefit. Huang et al. show that extracellular domain (ECD) cleavage of the ALK cell surface tyrosine kinase receptor mediates neuroblastoma cell migration through induction of an EMT phenotype. ECD cleavage is caused by MMP-9 whose inhibition leads to decreased cell migration.
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影响因子：
4.6
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泛神经母细胞瘤分析揭示了年龄和签名相关的驱动因素改变。
影响因子：
16.6
作者：
Brady SW;Liu Y;Ma X;Gout AM;Hagiwara K;Zhou X;Wang J;Macias M;Chen X;Easton J;Mulder HL;Rusch M;Wang L;Nakitandwe J;Lei S;Davis EM;Naranjo A;Cheng C;Maris JM;Downing JR;Cheung NV;Hogarty MD;Dyer MA;Zhang J
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Zhang J