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

Extracellular domain shedding of the ALK receptor mediates neuroblastoma cell migration.

Cell reports

Hao Huang, Alexander Gont, Lynn Kee, Ruben Dries, Kathrin Pfeifer, Bandana Sharma, David N Debruyne, Matthew Harlow, Satyaki Sengupta, Jikui Guan, Caleb M Yeung, Wenchao Wang, Bengt Hallberg, Ruth H Palmer, Meredith S Irwin, Rani E George

Affiliations

  1. Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
  2. Department of Pediatrics and Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
  3. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  4. Department of Pediatrics and Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada. Electronic address: [email protected].
  5. Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].

PMID: 34260934 PMCID: PMC8328392 DOI: 10.1016/j.celrep.2021.109363

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.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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