PTPN11, which encodes Src homology-2 domain-containing phosphatase 2 (SHP2), is the second most frequently mutated gene in high-risk neuroblastoma, and is often associated with amplified MYCN, suggesting that these two oncogenes act synergistically. To investigate this possibility, we programed aberrant Shp2 signaling using a transgenic approach to drive the expression of either mutationally activated ptpn11, wild-type Gab2 (an upstream regulator of SHP2) or the Gab2∆P85 mutant (which activates SHP2 signaling but not the PI3K pathway) in the peripheral sympathetic nervous system. We found that aberrant activation of Shp2 significantly accelerates the rate of neuroblastoma induction induced by overexpression of MYCN and increases tumor penetrance. These effects were mediated by increased activation of the Ras-Erk pathway and enhanced proliferation and survival of MYCN-induced hyperplastic neuroblasts in the zebrafish analogue of the human adrenal gland. Overexpression of wild-type Gab2 activated the PI3K-Akt pathway as well, leading to enhanced synergism with MYCN in neuroblastoma induction. Our results not only identify a cellular mechanism for the interaction of overexpressed MYCN with mutationally activated SHP2 in neuroblastoma initiation, but also provide in vivo evidence that SHP2 signaling might be activated by overexpression of GAB2 in neuroblastoma cases that lack PTPN11 mutations.