Background: Akt, also referred to as PKB or Rac, plays a critical role in controlling survival and apoptosis (1-3). This protein kinase is activated by insulin and various growth and survival factors to function in a wortmannin-sensitive pathway involving PI3 kinase (2,3). Akt is activated by phospholipid binding and activation loop phosphorylation at Thr308 by PDK1 (4) and by phosphorylation within the carboxy terminus at Ser473. The previously elusive PDK2 responsible for phosphorylation of Akt at Ser473 has been identified as mammalian target of rapamycin (mTOR) in a rapamycin-insensitive complex with rictor and Sin1 (5,6). Akt promotes cell survival by inhibiting apoptosis through phosphorylation and inactivation of several targets, including Bad (7), forkhead transcription factors (8), c-Raf (9), and caspase-9. PTEN phosphatase is a major negative regulator of the PI3 kinase/Akt signaling pathway (10). LY294002 is a specific PI3 kinase inhibitor (11). Another essential Akt function is the regulation of glycogen synthesis through phosphorylation and inactivation of GSK-3α and β (12,13). Akt may also play a role in insulin stimulation of glucose transport (12). In addition to its role in survival and glycogen synthesis, Akt is involved in cell cycle regulation by preventing GSK-3β-mediated phosphorylation and degradation of cyclin D1 (14) and by negatively regulating the cyclin dependent kinase inhibitors p27 Kip1 (15) and p21 Waf1/Cip1 (16). Akt also plays a critical role in cell growth by directly phosphorylating mTOR in a rapamycin-sensitive complex containing raptor (17). More importantly, Akt phosphorylates and inactivates tuberin (TSC2), an inhibitor of mTOR within the mTOR-raptor complex (18,19).
Background: PTEN (phosphatase and tensin homologue deleted on chromosome ten), also referred to as MMAC (mutated in multiple advanced cancers) phosphatase, is a tumor suppressor implicated in a wide variety of human cancers (1). PTEN encodes a 403 amino acid polypeptide originally described as a dual-specificity protein phosphatase (2). The main substrates of PTEN are inositol phospholipids generated by the activation of the phosphoinositide 3-kinase (PI3K) (3). PTEN is a major negative regulator of the PI3K/Akt signaling pathway (1,4,5). PTEN possesses a carboxy-terminal, noncatalytic regulatory domain with three phosphorylation sites (Ser380, Thr382, and Thr383) that regulate PTEN stability and may affect its biological activity (6,7). PTEN regulates p53 protein levels and activity (8) and is involved in G protein-coupled signaling during chemotaxis (9,10).
Background: AMPA- (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), kainate-, and NMDA- (N-methyl-D-aspartate) receptors are the three main families of ionotropic glutamate-gated ion channels. AMPA receptors (AMPARs) are composed of four subunits (GluA1-4), which assemble as homo- or hetero-tetramers to mediate the majority of fast excitatory transmissions in the central nervous system. AMPARs are implicated in synapse formation, stabilization, and plasticity (1). In contrast to GluA2-containing AMPARs, AMPARs that lack GluA2 are permeable to calcium (2). Post-transcriptional modifications (alternative splicing, nuclear RNA editing) and post-translational modifications (glycosylation, phosphorylation) result in a very large number of permutations, fine-tuning the kinetic properties and surface expression of AMPARs representing key pathways to mediate synaptic plasticity (3). During development and mature states, some synapses exhibit “silent synapses” that lack functional AMPAR-mediated transmission. Synapses become “unsilenced” by post-translational modification of GluAs, particularly GluA1, which alters its kinetic properties and/or surface expression while other synaptic components, such as other glutamate receptors like NMDARs and postsynaptic scaffolding proteins like PSD95, remain unaltered. Conversely, reducing the AMPAR kinetic properties and surface expression can silence synapses. Key post-translational modifications implicated in regulating these processes include phosphorylation of GluA1 at Ser831 and Ser845 (4). Research studies have implicated activity-dependent changes in AMPARs in a variety of diseases, including Alzheimer’s, amyotrophic lateral sclerosis (ALS), stroke, and epilepsy (1).