Akt信号转导路总结.docVIP

Akt (v-Akt Murine Thymoma Viral Oncogene)/ PKB (Protein Kinase-B) is a Serine/threonine Kinase that is involved in mediating various biological responses, such as inhibition of Apoptosis and stimulation of cell proliferation. Three mammalian isoforms are currently known: Akt1/PKB- Alpha, Akt2/PKB-Beta and Akt3/PKB-Gamma. All three isoforms of Akt share a common structure of three domains. The N-terminus of the protein is a PH (Pleckstrin Homology) domain, which interacts with membrane lipid products such as PIP2 (Phosphatidylinositol-3,4-Bisphosphate) and PIP3 (Phosphatidylinositol-3,4,5-Triphosphate). The PH domain is approximately 100 amino acids and plays a role in recognition by upstream kinases and membrane translocation of Akt. The center region of the protein is the Kinase domain, which has high similarity to other kinases. This domain contains a conserved threonine residue, which needs to be phosphorylated in order to activate Akt. The approximately 40 amino acids at the C-terminus of the protein form a regulatory domain that contains a proline rich region and a hydrophobic motif with a conserved sequence of FXX (F/Y)(S/T)(Y/F). In mammals, this hydrophobic motif is FPQFSY. The serine or threonine residue in this motif must also be phosphorylated to activate Kinase activity of Akt. This is also a conserved residue (Ref.1). Activation of Akt can begin with several events, mainly the binding of a Ligand to a Receptor in the cell membrane. Most common Ligands activating Akt include Growth factors, Cytokines, Mitogens and Hormones. Insulin and a variety of Growth factors bind to RTK (Receptor Tyrosine Kinase) and cause autophosphorylation of tyrosine residues on the intracellular domain of the receptor. PI3K (Phosphoinositol 3-Kinase) is recruited to the phosphotyrosine residues (consensus sequence pYXXM) via SH2 domains in the regulatory domain (p85), and is therefore targeted to the inner cell membrane. Binding of the p85 subunit of PI3K to the phosphorylated