Akt Pathway Proteins


 Akt Pathway Proteins Background

The Akt pathway or the PI3K-Akt pathway is a signal transduction pathway that promotes the survival and growth of extracellular signals. The key proteins include PI3K (phosphatidylinositol 3-kinase) and Akt (protein kinase B). The initial stimulation of a growth factor causes activation of cell surface receptors and phosphorylation of PI3K. The activated PI3K then phosphorylates the lipid on the plasma membrane to form a second messenger phosphatidylinositol (3,4,5)-triphosphate (PIP3). Akt is a serine/threonine kinase that is recruited to the membrane by interacting with these phosphoinositide docking sites, so it can be fully activated.

Activated Akt mediates downstream responses by phosphorylating a range of intracellular proteins, including cell survival, growth, proliferation, cell migration, and angiogenesis. This pathway is present in all cells of higher eukaryotes and is highly conserved. This pathway is highly regulated by a variety of mechanisms, often involving cross-talk with other signaling pathways. Problems mediated by the PI3K-Akt pathway can result in increased signaling activity. This is associated with a range of diseases such as cancer and type 2 diabetes. The primary antagonist of PI3K activity is PTEN (phosphatase and tensin homolog), a tumor suppressor that is frequently mutated or lost in cancer cells. Akt phosphorylates up to 100 different substrates, resulting in extensive effects on cells.

PI3K Activation

There are many types of phosphoinositide 3-kinase, but only class I is responsible for lipid phosphorylation in response to growth stimuli. Class 1 PI3K is a heterodimer consisting of a regulatory subunit p85 and a catalytic subunit p110, named after its molecular weight.

This pathway can be activated by a series of signals including hormones, growth factors and components of the extracellular matrix (ECM). It is stimulated by the binding of extracellular ligands to the receptor tyrosine kinase (RTK) in the plasma membrane, causing receptor dimerization and cross-phosphorylation of tyrosine residues in the intracellular domain. The regulatory subunit p85 binds to a phosphorylated tyrosine residue on the activating receptor via its Src homology 2 (SH2) domain. It then recruits the catalytic subunit p110 to form a fully active PI3K enzyme. Alternatively, the adaptor molecule Grb2 binds to the phospho-YXN motif of RTK and recruits p85 via a Grb2 associated binding (GAB) scaffold protein. The p110 subunit can also be raised independently of p85. For example, Grb2 can also bind to Ras-GEF Sos1, resulting in activation of Ras. Ras-GTP then activates the p110 subunit of PI3K. Other adaptor molecules such as the insulin receptor substrate (IRS) can also activate p110. PI3K can also be activated by a G protein-coupled receptor (GPCR), which directly binds PI3K via a G protein βγ dimer or Ras. In addition, Gα subunit activation activates Src-dependent integrin signaling of PI3K.

Akt Activation

Akt is present in the cytosol in an inactive conformation until the cells are stimulated and transferred to the plasma membrane. The Akt PH domain has a high affinity for the second messenger PI(3,4,5)P3, preferentially over other phosphoinositide binding. Therefore, PI3K activity is required for translocation of Akt to the membrane. Interaction with PI(3,4,5)P3 causes conformational changes and exposure of the phosphorylation site Thr308 in the kinase domain and Ser473 in the C-terminal domain. Phosphorylation of T308 is partially activated by PDK1. Complete activation requires phosphorylation of S473, which can be catalyzed by a variety of proteins, including phosphoinositide-dependent kinase 2 (PDK2), integrin-linked kinase (ILK), a mechanism target for rapamycin complex (mTORC) and DNA-dependent protein kinase (DNA-PK). The regulation of Ser473 phosphorylation is not fully understood, but may also be affected by autophosphorylation after Thr308 phosphorylation. After stimulation, by dephosphorylation of serine/threonine phosphatase, PIP3 levels are reduced and Akt activity is attenuated.

References:

1. Sardiello M.; et al. A gene network regulating lysosomal biogenesis and function. Science. 2009, 325 (5939): 473–477.

2. Basu S.; et al. " Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell. 2003,11 (1):11-23.