The kinase ALK stimulates the kinase ERK5 to promote the expression of the oncogene MYCN in neuroblastoma

Ganesh Umapathy, Abeer El Wakil, Barbara Witek, Louis Chesler, Laura Danielson, Xianming Deng, Nathanael S Gray, Mikael Johansson, Samuel Kvarnbrink, Kristina Ruuth, Christina Schönherr, Ruth H Palmer, Bengt Hallberg

Research output: Contribution to journalArticlepeer-review

Abstract

Anaplastic lymphoma kinase (ALK) is an important molecular target in neuroblastoma. Although tyrosine kinase inhibitors abrogating ALK activity are currently in clinical use for the treatment of ALK-positive (ALK(+)) disease, monotherapy with ALK tyrosine kinase inhibitors may not be an adequate solution for ALK(+) neuroblastoma patients. Increased expression of the gene encoding the transcription factor MYCN is common in neuroblastomas and correlates with poor prognosis. We found that the kinase ERK5 [also known as big mitogen-activated protein kinase (MAPK) 1 (BMK1)] is activated by ALK through a pathway mediated by phosphoinositide 3-kinase (PI3K), AKT, MAPK kinase kinase 3 (MEKK3), and MAPK kinase 5 (MEK5). ALK-induced transcription of MYCN and stimulation of cell proliferation required ERK5. Pharmacological or RNA interference-mediated inhibition of ERK5 suppressed the proliferation of neuroblastoma cells in culture and enhanced the antitumor efficacy of the ALK inhibitor crizotinib in both cells and xenograft models. Together, our results indicate that ERK5 mediates ALK-induced transcription of MYCN and proliferation of neuroblastoma, suggesting that targeting both ERK5 and ALK may be beneficial in neuroblastoma patients.

Original languageEnglish
Pages (from-to)ra102
JournalScience Signaling
Volume7
Issue number349
DOIs
Publication statusPublished - 28 Oct 2014

Keywords

  • Animals
  • Cell Line, Tumor
  • DNA Primers
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic
  • Green Fluorescent Proteins
  • Humans
  • Image Processing, Computer-Assisted
  • Immunoblotting
  • Immunohistochemistry
  • Immunoprecipitation
  • Magnetic Resonance Imaging
  • Mitogen-Activated Protein Kinase 7
  • Neuroblastoma
  • Nuclear Proteins
  • Oncogene Proteins
  • PC12 Cells
  • RNA Interference
  • Rats
  • Real-Time Polymerase Chain Reaction
  • Receptor Protein-Tyrosine Kinases

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