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. Display omitted •Activated Shp2 cooperates with MYCN to promote neuroblastomagenesis•Shp2 can be activated by overexpressed Gab2 in MYCN-driven neuroblastoma•Gab2 overexpression also activates the Ras-Erk pathway in neuroblastoma•Combined inhibition of MYCN and Mek-Erk signaling inhibits neuroblastoma cell growth Sequencing studies have identified few recurrent mutations in neuroblastomas. Zhang et al. uncover a non-mutational mechanism that enhances high-risk neuroblastomagenesis: aberrant SHP2 activation through overexpression of its upstream regulator, GAB2. Combined inhibition of MYCN and the GAB2-Shp2-Mek pathway may provide an avenue for improved targeted therapy of neuroblastoma.