PTEN Regulates PI(3,4)P(2) Signaling Downstream of Class I PI3K

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)P(3). PI(3,4,5)P(3) can be dephosphorylated by 3- or 5-phosphatases, the latter producing PI(3,4)P(2). The PTEN tumor suppressor is thought to function primarily as a PI(3,4,5)P(3) 3-phosphatase, limiting activation of this pathway. Here we show that PTEN also functions as a PI(3,4)P(2) 3-phosphatase, both in vitro and in vivo. PTEN is a major PI(3,4)P(2) phosphatase in Mcf10a cytosol, and loss of PTEN and INPP4B, a known PI(3,4)P(2) 4-phosphatase, leads to synergistic accumulation of PI(3,4)P(2), which correlated with increased invadopodia in epidermal growth factor (EGF)-stimulated cells. PTEN deletion increased PI(3,4)P(2) levels in a mouse model of prostate cancer, and it inversely correlated with PI(3,4)P(2) levels across several EGF-stimulated prostate and breast cancer lines. These results point to a role for PI(3,4)P(2) in the phenotype caused by loss-of-function mutations or deletions in PTEN.