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10q23. Also known as MMAC1 (mutated in multiple advanced cancers), PTEN is a dual function lipid and protein phosphatase composed of an N-terminal phosphatase domain, a C2 domain, and a C-terminal tail region containing a PSD-95/Dlg/ZO-1 (PDZ) homology domain. Its lipid phosphatase function negatively regulates PKB/Akt phosphorylation by dephosphorylating phosphatidylinositol (3,4,5) tris-phosphate (PtdIns(3,4,5)P3) and phosphatidyli-nositol (3,4) bisphosphate (PtdIns(3,4)P2), thereby restraining the PI3-kinase pathway. PTEN plays a critical role in the development of the central nervous system in mammals; early embryonic lethality results from homozygous PTEN deletions in transgenic mice [2].

An alternative lipid phosphatase regulating PKB/Akt is SH2-containing inositol-5-phosphatase (SHIP), an inositol 5'^phosphatase that hydrolyzes PI(3,4,5)P3 to PI(3,4)P2. SHIP-2 is widely expressed in non-hematopoietic cells, in contrast to SHIP-1, which is found primarily in hematopoeitic cells [3,4]. To date, SHIP has not been implicated in glioma-genesis and studies focusing on the relative roles of SHIP and PTEN as suppressors of the PI3-kinase pathway have identified PTEN as negatively regulating the PI-kinase/PKB/Akt cascade in leukemo-genesis [5].

Downstream Effectors PKB/Akt

PKB/Akt is a serine/threonine kinase that exists as three isoforms (a, and y). All three PKB/Akt isoforms are ubiquitously expressed in mammals, although levels of expression vary among tissues, with PKBy^displaying the most limited expression of all isoforms, expressed preferentially in lymphocytes. PtdIns(3,4)P2 and PtdIns(3,4,5)P3 produced by PI3-kinase bind to the pleckstrin homology domain of PKB/Akt, translocate PKB/Akt to the plasma membrane, and activate it [6]. PKB/Akt links PI3-kinase to effectors of cell-cycle regulation, metabolism, and invasion through the phosphorylation of many targets, some of which will be described more fully in this chapter. The cyclin-dependent kinase (cdk) inhibitor p27Kip1 [7], Bcl-2 family member Bad [8], caspase-9, FHKR, glycogen synthase kinase 3 (GSK3), TSC2, and RhoB are prominent targets directly phosphorylated by PKB/Akt.

With respect to metabolism, PKB/Akt transmits signals from IGF-1 to intracellular targets. In response to insulin stimulation, GSK3 is phosphorylated and inactivated by PKB in a PI3-kinase-dependent process, resulting in GSK3 phosphorylating and inactivating glycogen synthase.

PKB/Akt effects on cell-cycle progression are best understood at the level of G1 arrest; PKB/Akt-mediated phosphorylation of p27Kip1 results in cytoplasmic localization of p27Kip1 and loss of G1 arrest [7]. In addition to their documented effects on the G1 checkpoint, PI3-kinase and activated PKB/Akt can override the G2/M checkpoint [9,10] although the mechanisms underlying this response are to date unclear.

PKB/Akt shapes the anti-apoptotic response through its phosphorylation of Bad and caspase-9. Bad, a member of the Bcl-2 family, binds and antagonizes Bcl-2 and Bcl-X, inhibiting their anti-apoptotic potential [11]. Caspase-9, an apoptotic effector, is phosphorylated by PKB/Akt, resulting in the inhibition of cytochrome C-induced cleavage [12].

Transcriptional regulation is a mechanism by which PKB/Akt promotes survival. In response to IGF-1 signaling, the Forkhead family of transcription factors (FH or FoxO) are phosphorylated by PKB/ Akt, which results in nuclear exclusion and reduced transcriptional activity needed for promoting apoptosis [13-16].

The identification of new PKB/Akt-binding proteins adds to the apparent complexity of PKB/ Akt roles, and identifies potential therapeutic targets. Among these is Ft1, a protein shown to interact with

FIGURE 13.1 The PI3-kinase pathway. Signaling through growth factor receptors activates PI3-kinase, which produces PI(3,4,5)P3, a signaling messenger that recruits PKB/Akt to the membrane and, through activation of PDK-1, activates PKB/Akt. PKB/Akt, in turn, phosphorylates a number of targets, resulting in the wide range of cellular processes affected. These phosphorylation cascades are restrained by the activity of the tumor suppressor PTEN, a lipid and protein phosphatase that opposes PI3-kinase activity by dephosphorylating PI(3,4,5)P3. See Plate 13.1 in Color Plate Section.

FIGURE 13.1 The PI3-kinase pathway. Signaling through growth factor receptors activates PI3-kinase, which produces PI(3,4,5)P3, a signaling messenger that recruits PKB/Akt to the membrane and, through activation of PDK-1, activates PKB/Akt. PKB/Akt, in turn, phosphorylates a number of targets, resulting in the wide range of cellular processes affected. These phosphorylation cascades are restrained by the activity of the tumor suppressor PTEN, a lipid and protein phosphatase that opposes PI3-kinase activity by dephosphorylating PI(3,4,5)P3. See Plate 13.1 in Color Plate Section.

multi-level dysregulation of pi3-kinase: implications for gliomagenesis

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