PTEN Regulates PI(3,4)P₂ Signaling Downstream of Class I PI3K

Highlights

• PTEN is a PI(3,4)P₂ 3-phosphatase

• PTEN and INPP4B regulate PI(3,4)P₂ accumulation downstream of class I PI3K

• PTEN regulates PI(3,4)P₂-dependent activation of Akt and formation of invadopodia

• PI(3,4)P₂ signaling may play a role in the tumor suppressor function of PTEN

Summary

The PI3K signaling pathway regulates cell growth and movement and is heavily mutated in cancer. Class I PI3Ks synthesize the lipid messenger PI(3,4,5)P₃. PI(3,4,5)P₃ can be dephosphorylated by 3- or 5-phosphatases, the latter producing PI(3,4)P₂. The PTEN tumor suppressor is thought to function primarily as a PI(3,4,5)P₃ 3-phosphatase, limiting activation of this pathway. Here we show that PTEN also functions as a PI(3,4)P₂ 3-phosphatase, both in vitro and in vivo. PTEN is a major PI(3,4)P₂ phosphatase in Mcf10a cytosol, and loss of PTEN and INPP4B, a known PI(3,4)P₂ 4-phosphatase, leads to synergistic accumulation of PI(3,4)P₂, which correlated with increased invadopodia in epidermal growth factor (EGF)-stimulated cells. PTEN deletion increased PI(3,4)P₂ levels in a mouse model of prostate cancer, and it inversely correlated with PI(3,4)P₂ levels across several EGF-stimulated prostate and breast cancer lines. These results point to a role for PI(3,4)P₂ in the phenotype caused by loss-of-function mutations or deletions in PTEN.