A central and unresolved question in cancer is how deregulated signaling leads to acquisition of an invasive cellular phenotype. Here, we modeled the invasive transition as a theoretical switch between focal adhesions and extracellular matrix (ECM)-degrading invadopodia and built molecular interaction network models of each structure. To identify upstream regulatory hubs, we added first degree binding partners and applied graph theoretic analyses. Comparison of the results to clustered reverse phase protein array signaling data from head and neck carcinomas led us to choose phosphatidylinositol 3-kinase (PI3K) and protein kinase C alpha (PKCα) for further analysis. Consistent with a previous report, PI3K activity promoted both the formation and activity of invadopodia. Furthermore, PI3K induction of invadopodia was increased by overexpression of SH2 domain-containing inositol 5′-phosphatase 2 (SHIP2), suggesting that a major part of the mechanism is synthesis of PI(3,4,5)P3, a precursor for PI(3,4)P2, which promotes invadopodia formation. Knockdown of PKCα led to divergent effects on invadopodia formation, depending on the activation state of PI3K. Loss of PKCα inhibited invadopodia formation in cells with wild-type PI3K pathway status. Conversely, in cells with either activating PI3K mutants or lacking the endogenous opposing enzyme phosphatase and tensin homolog (PTEN), PKCα knockdown increased invadopodia formation. Investigation of the mechanism revealed that a negative feedback loop from PKCα dampened PI3K activity and invasive behavior in cells with genetic overactivation of the PI3K pathway. These studies demonstrate the potential of network modeling as a discovery tool and identify PI3K and PKCα as critical interacting regulators of invasive behavior.