PUBLICATION

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

Authors
Zhang, X., Dong, Z., Zhang, C., Ung, C.Y., He, S., Tao, T., Oliveira, A.M., Meves, A., Ji, B., Look, A.T., Li, H., Neel, B.G., Zhu, S.
ID
ZDB-PUB-170323-5
Date
2017
Source
Cell Reports   18: 2932-2942 (Journal)
Registered Authors
Dong, Zhiwei, He, Shuning, Look, A. Thomas, Tao, Ting, Zhang, Xiaoling, Zhu, Shizhen
Keywords
Gab2, MYCN, RAS-ERK pathway, Shp2, neuroblastoma, ptpn11, zebrafish
MeSH Terms
  • Carcinogenesis/drug effects
  • Carcinogenesis/genetics
  • Carcinogenesis/pathology
  • Animals
  • Apoptosis/drug effects
  • Apoptosis/genetics
  • Neuroblastoma/metabolism*
  • Neuroblastoma/pathology*
  • Zebrafish/metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism*
  • Gene Amplification/drug effects
  • N-Myc Proto-Oncogene Protein/metabolism*
  • Gene Expression Profiling
  • Carrier Proteins/metabolism*
  • Mutation/genetics
  • Zebrafish Proteins/metabolism*
  • Cell Proliferation/drug effects
  • Risk Factors
  • Animals, Genetically Modified
  • Carbazoles/pharmacology
  • MAP Kinase Signaling System/drug effects
  • Humans
(all 22)
PubMed
28329685 Full text @ Cell Rep.
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.
Genes / Markers
Figures
Figure Gallery (10 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
zdf16Tg (AB)controlAdult
zdf16Tg (AB)standard conditionsDays 21-29
zdf16Tg (AB)standard conditionsDays 30-44
zdf16Tg (AB)standard conditionsDays 30-44
zdf16Tg (AB)standard conditionsDays 30-44 to Adult
zdf16Tg (AB)standard conditionsAdult
zdf16Tg (AB)chemical treatment by injection: CBL0137Adult
zdf16Tg (AB)chemical treatment by injection: CBL0137Adult
zdf16Tg (AB)chemical treatment by injection: CBL0137Adult
zdf16Tg (AB)chemical treatment by injection: CBL0137Adult
1 - 10 of 30
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
zdf16TgTransgenic Insertion
    zdf22TgTransgenic Insertion
      zf738TgTransgenic Insertion
        zf739TgTransgenic Insertion
          1 - 4 of 4
          Show
          Human Disease / Model
          Human Disease Fish Conditions Evidence
          neuroblastomazdf16Tg (AB)standard conditionsTAS
          1 - 1 of 1
          Show
          Sequence Targeting Reagents
          No data available
          Fish
          Fish
          zdf16Tg (AB)
          zdf16Tg; zf738Tg (AB)
          zdf16Tg; zf739Tg (AB)
          zdf22Tg (AB)
          zf738Tg (AB)
          1 - 5 of 5
          Show
          Antibodies
          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          EGFPEFGEGFP
          mCherryEFGmCherry
          1 - 2 of 2
          Show
          Mapping
          No data available
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          Citation
          Zhang, X., Dong, Z., Zhang, C., Ung, C.Y., He, S., Tao, T., Oliveira, A.M., Meves, A., Ji, B., 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. 18:2932-2942.