By construction of relevant EGFRvIII-expressing GBM cells, we show that, in the environment of hypoxia and vitronectin-enrichment in vitro, integrin β3 interacts directly with EGFRVIII and activates a SRC/FAK/EGFRvIII signaling axis to promote GBM cell invasion. The gene discussed is PTK2; the disease is glioblastoma.