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The PI3K‐AKT signaling pathway regulates cell survival, proliferation, and migration. An abnormal activation of PI3K plays an important role in cancer development. Here, we identify TRAF6 as a potent E3 ubiquitin ligase for the PI3K catalytic subunit PIK3CA (p110α). TRAF6 interacts with PIK3CA and promotes its nonproteolytic polyubiquitination under serum stimulation. TRAF6 ubiquitinates both individual and regulatory subunit‐bound PIK3CA but does not ubiquitinate the regulatory subunit of PI3K. The examination of TRAF6 mRNA expression revealed its upregulation in multiple human malignancies. We demonstrate that overexpression of TRAF6 greatly enhances PI3K activation, leading to an increase in AKT phosphorylation and cell growth. We conclude that TRAF6 is a novel PIK3CA regulator whose deregulated overexpression represents a mechanism for PI3K overactivation in tumors. [ABSTRACT FROM AUTHOR]