her subdivided into class IA and class IB, based on subunit composition and activation mode. Class I enzymes are heterodimers composed of a catalytic and a regulatory subunit. The three catalytic subunits of class IA are p110alpha, gamma and delta, encoded by Pik2ca, Pik3cb and Pik3cd, respectively. The catalytic subunit binds a regulatory subunit represented by p85alpha, p85beta or p55gamma, encoded by Pik3r1, Pik3r2 and Pik3r3, respectively. The alpha and beta catalytic subunits and regulatory p85alpha and beta are ubiquitously expressed, whereas the catalytic delta and regulatory p55gamma have a more restricted expression pattern. Class IB consists of catalytic p110gamma and regulatory p101 and p84 regulatory subunits. Unlike class IA, which largely responds to activated RTKs, although p110beta can respond to both RTKs and G protein-coupled receptors (GPCRs), the class IB responds to activated GPCRs. By far the best studied system is class IA, particularly in the context of its main downstream mediator - the AKT kinases, known as PKB. The PI3k-Akt signaling is presented in greater detail.

Receptor tyrosine kinases (RTKs) are activated by phosphorylation of particular tyrosine residues which are then recognized by proteins with Src homology 2 (SH2) domains, of which there are two in the regulatory PI3K subunits. Recruitment of the lipid kinase at the membrane allows for the phosphorylation of PIP2 (PIdIns(4,5)₂) to form the second messenger PIP3 (PtdIns(3,4,5)₃). PIP3 is recognized by proteins with plekstrin homolog (PH) domains; in this system the Akt kinases and Pdpk1 kinase. Translocation of AKT enzymes to the membrane leads to their activation via two phosphorylation events. Pdpk1 phosphorylates a threonine in the kinase domain of Akt, (T308 in Akt1). A second phosphorylation, a serine residue in the hydrophobic region (S473 in Akt1), is required for full activation. The second phosphorylation event is carried out by the mTOR kinase in the mTORC2 complex of the mTOR pathway. Once activated, the Akt members translocate to the cytoplasm and the nucleus to phosphorylate and regulate a large number of substrates, either activating or inhibiting their function. Though the specificity of substrates and the discrete subcellular localization appear to be isoform-dependent, collectively the PI3K-Akt pathway regulates a wide spectrum of pathways and processes that include metabolism, cell proliferation and migration, growth and survival. Major substrates include glycogen synthase kinase 3 isoforms (Gsk3 alpha and beta), components of mTOR and of insulin-dependent glucose transport pathways, proapoptotic proteins such as Bad, Bim and Bax, forhkead transcription factors, among others.

The activity of Akt is tightly regulated and under unstimulated conditions, PIP3 is subject to the action of phosphatases, of which Pten plays a prominent role. Pten dephosphorylates the 3-position of PIP3, back to PIP2. The 5-position phosphatases include Inpp5d and Inppl1, known as Ship1 and 2, respectively. Pten dephosphorylates both lipids and proteins, and among its protein targets are the Gsk3 isoforms that Akt phosphorylates. Phosphorylation of Gsk3s inhibits their activity, dephosphorylation restores it. Phosphorylation of Gsk3 substrates, many times coupled to their ubiquitination via a Btrc adaptor, followed by subsequent proteasomal degradation, is observed in systems such as canonical Wnt, hedgehog and Nfe2l2 (known as Nrf2) signaling pathways. Akt, via inhibitory Gsk3 phosphorylation activates the Nfe2l2 pathway, one of the most important regulators of antioxidant and electrophilic stress responses. Interestingly, reactive oxygen species (ROS) and electrophiles that prompt the Nfe2l2 pathway by inhibiting its main redox sensor, Keap1, can also inhibit Pten via modification of a reactive cysteine in the active site. Pten, a candidate tumor suppressor, is linked to various types of cancer due to mutations and/or deletions. Akt enzymes are also subject to dephosphorylation. The two phosphorylation positions required for full Akt activation, T308 and S473, are targeted by PP2A and Phlpp1/2, respectively. Phlpp1 targets Akt2 and 3, Phlpp2 targets Akt1 and 3. In turn, Phlpp enzymes can be targets of Gsk3 isoforms and Btrc-mediated degradation. By targeting Gsk3, Akt can modulate its own activity.

Deregulation of PI3K-AKT signaling is associated with several conditions, primarily cancer, and in breast cancer with a rather high frequency. PTEN phosphatase, usually a tumor suppressor, is lost in many cancers. Mutations and deletions in the Pten gene are also found in non-cancerous tumors. Deregulation of the pathway and/or its cross-talk with mTOR signaling is associated with brain conditions and neurodegenerative diseases. To see the ontology report for annotations, GViewer amd download, click here....(less)