Information from multiple signaling axes is integrated in the determination of cellular phenotypes. Here, we demonstrate this aspect of cellular decision making in glioblastoma multiforme (GBM) cells by investigating the multivariate signaling regulatory functions of the protein tyrosine phosphatase SHP2. Specifically, we demonstrate that SHP2's ability to simultaneously drive ERK and antagonize STAT3 pathway activities produces qualitatively different effects on the phenotypes of proliferation and resistance to EGFR and c-MET co-inhibition. While the ERK and STAT3 pathways independently promote proliferation and resistance to EGFR and c-MET co-inhibition, SHP2-driven ERK activity is dominant in driving cellular proliferation, and SHP2's antagonism of STAT3 phosphorylation prevails in promoting GBM cell death in response to EGFR and c-MET co-inhibition. Interestingly, the extent of these SHP2 signaling regulatory functions is diminished in glioblastoma cells expressing sufficiently high levels of the EGFR variant III (EGFRvIII) mutant, which is commonly expressed in GBM. In cells and tumors expressing EGFRvIII, SHP2 also antagonizes EGFRvIII and c-MET phosphorylation and drives expression of HIF-1/2α, adding complexity to the evolving understanding of SHP2's regulatory functions in GBM.