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

Xiaoling Zhang1, Zhiwei Dong1, Cheng Zhang2

  • 1Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, MN 55902, USA.

Cell Reports
|March 23, 2017
PubMed

Insights

Src-homology-2-domain-containing phosphatase 2 (SHP2) and Gab2 cooperate with MYCN in neuroblastoma development. Targeting MYCN and the SHP2-Ras-ERK pathway may offer new therapies for high-risk neuroblastoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • MYCN amplification drives high-risk neuroblastoma.
  • The role of SHP2 (PTPN11) in MYCN-driven neuroblastoma is not fully understood.
  • A plausible mechanism linking SHP2 to neuroblastoma pathogenesis is needed.

Purpose of the Study:

  • To investigate the role of SHP2/PTPN11 in MYCN-driven neuroblastoma.
  • To elucidate the underlying molecular mechanisms.
  • To explore potential therapeutic targets.

Main Methods:

  • Utilized a zebrafish model of MYCN-overexpressing neuroblastoma.
  • Assessed the impact of mutant ptpn11 and Gab2 overexpression on neuroblast proliferation and tumor development.
  • Analyzed the activation of the Shp2-Ras-Erk pathway.

Main Results:

  • Mutant ptpn11 expression accelerated neuroblastomagenesis and increased tumor penetrance in MYCN transgenic zebrafish.
  • Gab2 overexpression, a Shp2 activator, mimicked this effect in tumors with wild-type ptpn11.
  • Gab2 activated the Shp2-Ras-Erk pathway, enhancing neuroblastoma induction.

Conclusions:

  • MYCN cooperates with either GAB2-activated or mutant SHP2 in human neuroblastomagenesis.
  • Combined inhibition of MYCN and the SHP2-RAS-ERK pathway shows promise for targeted therapy in high-risk neuroblastoma.
Keywords:
Gab2MYCNRAS-ERK pathwayShp2neuroblastomaptpn11zebrafish

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