Akt/PKB signaling pathway

The Akt Pathway, or PI3K-Akt Pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K (phosphatidylinositol 3-kinase) and Akt (Protein Kinase B). The Akt Pathway, or PI3K-Akt Pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K (phosphatidylinositol 3-kinase) and Akt (Protein Kinase B). Initial stimulation by one of the growth factors causes activation of a cell surface receptor and phosphorylation of PI3K. Activated PI3K then phosphorylates lipids on the plasma membrane, forming second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3). Akt, a serine/threonine kinase, is recruited to the membrane by interaction with these phosphoinositide docking sites, so that it can be fully activated.Activated Akt mediates downstream responses, including cell survival, growth, proliferation, cell migration and angiogenesis, by phosphorylating a range of intracellular proteins. The pathway is present in all cells of higher eukaryotes and is highly conserved. The pathway is highly regulated by multiple mechanisms, often involving cross-talk with other signalling pathways. Problems with PI3K-Akt pathway regulation can lead to increase in signalling activity. This has been linked to a range of diseases such as cancer and type II diabetes. A major antagonist of PI3K activity is PTEN (phosphatase and tensin homolog), a tumour suppressor which is often mutated or lost in cancer cells. Akt phosphorylates as many as 100 different substrates, leading to a wide range of effects on cells. There are multiple types of phosphoinositide 3-kinase but only class I are responsible for lipid phosphorylation in response to growth stimuli. Class 1 PI3Ks are heterodimers composed of a regulatory subunit p85 and a catalytic subunit p110, named by their molecular weights. The pathway can be activated by a range of signals, including hormones, growth factors and components of the extracellular matrix (ECM). It is stimulated by binding of an extracellular ligand to a receptor tyrosine kinase (RTK) in the plasma membrane, causing receptor dimerization and cross-phosphorylation of tyrosine residues in the intracellular domains. The regulatory subunit p85 binds to phosphorylated tyrosine residues on the activated receptor via its Src homology 2 (SH2) domain. It then recruits the catalytic subunit p110 to form the fully active PI3K enzyme. Alternatively, adaptor molecule Grb2 binds to phospho-YXN motifs of the RTK and recruits p85 via Grb2-associated binding (GAB) scaffold protein. The p110 subunit can also be recruited independently of p85. For example, Grb2 can also bind the Ras-GEF Sos1, leading to activation of Ras. Ras-GTP then activates the p110 subunit of PI3K. Other adaptor molecules such as insulin receptor substrate (IRS) can also activate p110. PI3K can also be activated by G protein-coupled receptors (GPCR), via G-protein βγ dimers or Ras which bind PI3K directly. In addition, the Gα subunit activates Src-dependent integrin signalling which can activate PI3K. Activated PI3K catalyses the addition of phosphate groups to the 3'-OH position the inositol ring of phosphoinositides (PtdIns), producing three lipid products, PI(3)P, PI(3,4)P2 and PI(3,4,5)P3: Phosphatidylinositol (PI) → PI 3-phosphate, (PI(4)P) → PI 3,4-bisphosphate, (PI(4,5)P2) → PI 3,4,5-triphosphate