The paradoxical functions of PYK2 as either an oncogene or tumor suppressor are principally governed by three interconnected determinants: (1) Tissue-specific interacting partners—in GC, PYK2 forms a nuclear complex with p53 and Mdm2 to drive p53 ubiquitination and degradation, thereby disabling a critical tumor-suppressive checkpoint (38–40). The gene discussed is PTK2B; the disease is neoplasm.