Critical Role for GAB2 in Neuroblastoma Pathogenesis through the Promotion of SHP2/MYCN Cooperation

Xiaoling Zhang, Zhiwei Dong, Cheng Zhang, Choong Yong Ung, Shuning He, Ting Tao, Andre M. Oliveira, Alexander Meves, Baoan D Ji, A. Thomas Look, Hu Li, Benjamin G. Neel, Shizhen Zhu

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Growing evidence suggests a major role for Src-homology-2-domain-containing phosphatase 2 (SHP2/PTPN11) in MYCN-driven high-risk neuroblastoma, although biologic confirmation and a plausible mechanism for this contribution are lacking. Using a zebrafish model of MYCN-overexpressing neuroblastoma, we demonstrate that mutant ptpn11 expression in the adrenal gland analog of MYCN transgenic fish promotes the proliferation of hyperplastic neuroblasts, accelerates neuroblastomagenesis, and increases tumor penetrance. We identify a similar mechanism in tumors with wild-type ptpn11 and dysregulated Gab2, which encodes a Shp2 activator that is overexpressed in human neuroblastomas. In MYCN transgenic fish, Gab2 overexpression activated the Shp2-Ras-Erk pathway, enhanced neuroblastoma induction, and increased tumor penetrance. We conclude that MYCN cooperates with either GAB2-activated or mutant SHP2 in human neuroblastomagenesis. Our findings further suggest that combined inhibition of MYCN and the SHP2-RAS-ERK pathway could provide effective targeted therapy for high-risk neuroblastoma patients with MYCN amplification and aberrant SHP2 activation.

Original languageEnglish (US)
Pages (from-to)2932-2942
Number of pages11
JournalCell Reports
Volume18
Issue number12
DOIs
StatePublished - Mar 21 2017

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Keywords

  • Gab2
  • MYCN
  • neuroblastoma
  • ptpn11
  • RAS-ERK pathway
  • Shp2
  • zebrafish

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhang, X., Dong, Z., Zhang, C., Ung, C. Y., He, S., Tao, T., Oliveira, A. M., Meves, A., Ji, B. D., Look, A. T., Li, H., Neel, B. G., & Zhu, S. (2017). Critical Role for GAB2 in Neuroblastoma Pathogenesis through the Promotion of SHP2/MYCN Cooperation. Cell Reports, 18(12), 2932-2942. https://doi.org/10.1016/j.celrep.2017.02.065