Extracellular domain shedding of the ALK receptor mediates neuroblastoma cell migration

Cell Rep. 2021 Jul 13;36(2):109363. doi: 10.1016/j.celrep.2021.109363.


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.

Keywords: ALK; MMP-9; cleavage; epithelial-to-mesenchymal transition; extracellular domain; migration; neuroblastoma; receptor tyrosine kinase; wild-type ALK; β-catenin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anaplastic Lymphoma Kinase / antagonists & inhibitors
  • Anaplastic Lymphoma Kinase / chemistry*
  • Anaplastic Lymphoma Kinase / genetics
  • Anaplastic Lymphoma Kinase / metabolism*
  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cell Movement*
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Glycine / chemistry
  • HEK293 Cells
  • Humans
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics
  • NIH 3T3 Cells
  • Neoplasm Invasiveness
  • Neuroblastoma / genetics
  • Neuroblastoma / pathology*
  • Protein Binding
  • Protein Domains


  • Anaplastic Lymphoma Kinase
  • Matrix Metalloproteinase 9
  • Glycine