Lipid Phosphatases

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PTEN is a lipid phosphatase whose major substrate is phosphatidylinositol -3,4,5-triphosphate (PIP3). Upon growth factors, cytokines or antigen stimulation, PIP3 is generated by the phosphoinositide-3-kinase (PI3K), thereby recruiting and activating the downstream kinase Akt through PDK1-mediated phosphorylation. Akt is involved in multiple cellular functions, like proliferation, oncogenesis and antiapoptosis [92]. By reducing the pool of PIP3, PTEN is involved in the negative regulation of the Akt pathway and thus suppress tumorigenesis. PTEN is one of the most frequently mutated tumor suppressor in human cancer, and a large number of tumors exhibit reduced PTEN expression [93, 94]. Pten^+/- mice develop lymphoproliferative disorders similar to that observed in lpr and gld mice, and lymphocytes from these mice are unresponsive to CD95-mediated apoptosis [95].  In long term activated T cells (which are resistant to CD95-mediated apoptosis), increased phosphorylation of Akt due to the loss of PTEN expression accounts for a reduced DISC formation [96]. In the same way, T cells expressing active Akt are resistant to CD95-induced apoptosis due to impaired recruitment of caspase-8 to the DISC [97]. The underlying mechanisms are yet unknown. It thus appears that PTEN plays a key role in the modulation of the CD95 pathway through the control of Akt activation.