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

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.

• Authors: Xiaoling Zhang, Zhiwei Dong, Cheng Zhang, Choong Yong Ung, Shuning He, Ting Tao, Andre M Oliveira, Alexander Meves, Baoan Ji, A Thomas Look, Hu Li, Benjamin G Neel, Shizhen Zhu
• Journal: Cell reports (Cell Rep) Vol. 18 Issue 12 Pg. 2932-2942 (03 21 2017) ISSN: 2211-1247 [Electronic] United States
• PMID: 28329685 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• CBLC137
• Carbazoles
• Carrier Proteins
• Gab2 protein, zebrafish
• N-Myc Proto-Oncogene Protein
• Zebrafish Proteins
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• protein tyrosine phosphatase, non-receptor type 11, a, zebrafish

Topics

• Animals
• Animals, Genetically Modified
• Apoptosis (drug effects, genetics)
• Carbazoles (pharmacology)
• Carcinogenesis (drug effects, genetics, pathology)
• Carrier Proteins (metabolism)
• Cell Proliferation (drug effects)
• Gene Amplification (drug effects)
• Gene Expression Profiling
• Humans
• MAP Kinase Signaling System (drug effects)
• Mutation (genetics)
• N-Myc Proto-Oncogene Protein (metabolism)
• Neuroblastoma (metabolism, pathology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (metabolism)
• Risk Factors
• Zebrafish (metabolism)
• Zebrafish Proteins (metabolism)