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- W3178444894 abstract "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." @default.
- W3178444894 created "2021-07-19" @default.
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- W3178444894 date "2021-07-01" @default.
- W3178444894 modified "2023-10-16" @default.
- W3178444894 title "Extracellular domain shedding of the ALK receptor mediates neuroblastoma cell migration" @default.
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- W3178444894 doi "https://doi.org/10.1016/j.celrep.2021.109363" @default.
- W3178444894 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8328392" @default.
- W3178444894 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34260934" @default.
- W3178444894 hasPublicationYear "2021" @default.
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