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Extracellular domain shedding of the ALK receptor mediates neuroblastoma cell migration
- Source :
- Cell reports, Cell Reports, Vol 36, Iss 2, Pp 109363-(2021)
- Publication Year :
- 2021
-
Abstract
- SUMMARY 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.<br />Graphical abstract<br />In brief 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.
- Subjects :
- migration
Receptor tyrosine kinase
Mice
Neuroblastoma
0302 clinical medicine
Cell Movement
Anaplastic lymphoma kinase
Anaplastic Lymphoma Kinase
cleavage
Biology (General)
Receptor
0303 health sciences
biology
Chemistry
Cell biology
Gene Expression Regulation, Neoplastic
Matrix Metalloproteinase 9
030220 oncology & carcinogenesis
Female
MMP-9
Protein Binding
Epithelial-Mesenchymal Transition
QH301-705.5
Glycine
Cleavage (embryo)
General Biochemistry, Genetics and Molecular Biology
Article
03 medical and health sciences
Downregulation and upregulation
Protein Domains
Cell surface receptor
Cell Line, Tumor
Extracellular
medicine
Animals
Humans
Neoplasm Invasiveness
Amino Acid Sequence
030304 developmental biology
Base Sequence
Gene Expression Profiling
Cell Membrane
medicine.disease
Mice, Inbred C57BL
Disease Models, Animal
HEK293 Cells
ALK
Mutation
biology.protein
receptor tyrosine kinase
NIH 3T3 Cells
Subjects
Details
- Language :
- English
- ISSN :
- 22111247
- Volume :
- 36
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Cell reports
- Accession number :
- edsair.doi.dedup.....53d457a5a4675766e50fe43205b1844a