The canonical action of the p85α regulatory subunit of phosphatidylinositol 
3-kinase (PI3K) is to associate with the p110α catalytic subunit to allow 
stimuli-dependent activation of the PI3K pathway. We elucidate a 
p110α-independent role of homodimerized p85α in the positive regulation of PTEN 
stability and activity. p110α-free p85α homodimerizes via two intermolecular 
interactions (SH3:proline-rich region and BH:BH) to selectively bind 
unphosphorylated activated PTEN. As a consequence, homodimeric but not monomeric 
p85α suppresses the PI3K pathway by protecting PTEN from E3 ligase WWP2-mediated 
proteasomal degradation. Further, the p85α homodimer enhances the lipid 
phosphatase activity and membrane association of PTEN. Strikingly, we identified 
cancer patient-derived oncogenic p85α mutations that target the homodimerization 
or PTEN interaction surface. Collectively, our data suggest the equilibrium of 
p85α monomer-dimers regulates the PI3K pathway and disrupting this equilibrium 
could lead to disease development.