The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes cell survival and growth in response to extracellular signals.
AKT is the key node of the phoshatidylinositol 3 kinase (PI3K)-AKT-PTEN signaling pathway.
Akt also known as protein kinase B.
Growth factors cause activation of a cell surface receptor and phosphorylation of PI3K.
The PI3K pathway is implicated in almost half of all malignant diseases, and among the most frequently activated pathways in human cancers.
They are three classes of PI3K inhibitors.
Activated Akt mediates downstream responses by phosphorylating a range of intracellular proteins affecting cell survival, growth, proliferation, cell migration and angiogenesis.
Overactivation of the PI3K-AKT-PTEN pathway occurs in approximately half of hormone receptor positive, HER2 negative breast cancers by means of activating mutations in PIK3CA and AKT1 and inactivating alterations in PTEN.
Activating mutations and PIK3CA occur approximately 30 to 45% of hormone receptor positive breast cancers.
Alterations in this pathway may present at the time of cancer recurrence, and can be acquired by means of previous treatment, including CDK/6 inhibitors.
AKT signaling may also be activated in the absence of genetic alterations in patients with endocrine resistance.
The pathway is present in all cells and is highly regulated by cross-talk with other signaling pathways.
PI3K-Akt pathway abnormal regulation can lead to an increase in signaling activity linked to diseases such as cancer and type 2 diabetes.
PTEN (phosphatase and tensin homolog) is a major antagonist of PI3K activity, a tumor suppressor which is often mutated or lost in cancer cells.
Akt phosphorylates as many as 100 different substrates.
Akt phosphorylation leads to a wide range of effects on cells.
While multiple types of phosphoinositide 3-kinase exist, only class I are responsible for lipid phosphorylation in response to growth stimuli.
The PI3K-Akt pathway can be activated by a range of signals, including hormones, growth factors and components of the extracellular matrix.
PI3K can also be activated by G protein-coupled receptors (GPCR), or Ras which bind PI3K directly.
Src-dependent integrin signaling can activate PI3K.
Activated PI3K catalyses the addition of phosphate groups to the 3′-OH position of phosphoinositides producing three lipid products.
These phosphorylated lipids are anchored to the plasma membrane, where they can directly bind intracellular proteins.
Akt resides in the cytoplasm in an inactive conformation.
When the cell is stimulated and it translocates to the plasma membrane.
The Akt domain has a high affinity for second messenger PI3, binding to it preferentially over other phosphoinositides.
PI3K activity is essential for translocation of Akt to the membrane.
PI3K is the major mode of Akt activation, but other tyrosine or serine/threonine kinases have been shown to activate Akt directly.
The PI3K-Akt pathway has many downstream effects and is regulated.
Phosphatase and tensin homolog (PTEN) antagonises PI3K, while loss of PTEN function leads to over-activation of Akt and is common in cancer cells.
PTEN is a tumour suppressor gene.
The PI3K-Akt pathway regulates PTEN levels by affecting its transcription and activity.
Transcription factor NF-κB, activated by Akt, regulates peroxisome proliferator-activated receptor delta (PPARβ/δ) agonists and tumor necrosis factor α (TNFα), which in turn repress PTEN expression.
When Akt is activated, PTEN is repressed in a positive feedback loop.
Actived Akt translocates from the plasma membrane to the cytosol and nucleus, where many of its substrates reside.
It regulates a wide range of proteins by phosphorylation, which can be
inhibitory or stimulatory, either suppressing or enhancing the activity of target proteins.
Akt is involved promoting cell survival or blocking apoptosis.
Activated Akt influences many factors involved in apoptosis, either by transcription regulation or direct phosphorylation.
Akt inhibits transcription factors in the nucleus that promote cell death genes, and enhances transcription of anti-apoptotic genes, positively regulates some transcription factors to allow expression of pro-survival genes.
Akt negatively regulates pro-apoptotic proteins by direct phosphorylation.
Akt promotes G1-S phase cell cycle progression, preventing the phosphorylation and degradation of cyclin D1.
Akt promotes G1 phase progression, and promotes cyclin D1 translation via indirect activation of mTOR.
mTOR increases translation of cyclin D1.
Akt both indirectly and directly regulates cyclin-dependent kinase inhibitors, allowing cell cycle progression.
Akt phosphorylates many proteins involved in polymerization and stabilization of the actin cytoskeleton.
Under oxidative stress, promotion of Akt/PKB signaling pat activation increases the biological function of cells under oxidative stress.
Activation of Akt, either via PI3K or independently of PI3K, is often associated with malignancy.
There are gene amplifications of the Akt isoforms in many types of cancer, including glioblastoma, ovarian, pancreatic and breast cancers.
Akt is also up-regulated in terms of mRNA production in breast and prostate cancer.
Functional inactivation of PTEN, the major PI3K antagonist, can occur in cancer cells by point mutation, gene deletion or epigenetic mechanisms.
Mutation in the pathway can also affect receptor tyrosine kinases, growth factors, Ras and the PI3K p110 subunit, leading to abnormal signaling activity.
Therefore, many of the proteins in the pathway are targets for cancer therapeutics.
In addition to its effects on cell survival and cell cycle progression, the PI3K-Akt pathway promotes other characteristics of cancer cells.
Hyperactivity of PI3K-Akt pathway promotes the epithelial-mesenchymal transition (EMT) and metastasis due to its effects on cell migration.
Akt is activated downstream of vascular endothelial growth factor (VEGF) in endothelial cells in the lining of blood vessels, promoting survival and growth of malignant cells.
Akt contributes to angiogenesis by activating endothelial nitric oxide synthase, increasing production of nitric oxide (NO).
PI3K-Akt signaling pathway increases translation of hypoxia-inducible factor α (HIF1α and HIF2α) transcription factors via mTOR.
HIF promotes gene expression of VEGF and glycolytic enzymes, allowing metabolism in oxygen-depleted environments.
An increase in Akt signaling in malignant cells correlates with an increase in glucose metabolism, compared to normal cells.
Cancer cells favor glycolysis for energy production over mitochondrial oxidative phosphorylation, even when oxygen supply ample (Warburg effect, or aerobic glycolysis.
Akt affects glucose metabolism by increasing translocation of glucose transporters GLUT1 and GLUT4 to the plasma membrane.
Akt increases hexokinase expression and phosphorylating GSK3 which stimulates glycogen synthesis.