Malek, MouhannadKielkowska, AnnaChessa, TamaraAnderson, Karen E.Barneda, DavidPir, PınarNakanishi, HirokiEguchi, SatoshiKoizumi, AtsushiSasaki, JunkoJuvin, VéroniqueKiselev, Vladimir Y.Niewczas, IzabellaGray, AlexanderValayer, AlexandreSpensberger, DominikImbert, MarineFelisbino, Sergio [UNESP]Habuchi, TomonoriBeinke, SorenCosulich, SabinaLe Novère, NicolasSasaki, TakehikoClark, JonathanHawkins, Phillip T.Stephens, Len R.2018-12-112018-12-112017-11-02Molecular Cell, v. 68, n. 3, p. 566-580.e10, 2017.1097-41641097-2765http://hdl.handle.net/11449/175364The 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. Malek et al. show that the tumor suppressor PTEN acts as a PI(3,4)P2 3-phosphatase within the growth factor-stimulated PI3K signaling network, in addition to its accepted role as a PI(3,4,5)P3 3-phosphatase. This suggests that specific PI(3,4)P2 effector functions, such as invadopodia formation, play a role in the PTEN-loss-of-function phenotype.566-580.e10engcancerINPP4BinvadopodiaPI(3,4)P2PI(3,4,5)P3PI3KprostatePTENSHIP2Artigo10.1016/j.molcel.2017.09.024Acesso restrito2-s2.0-85031821662