Yves Pommier, Mirit I. Aladjem and Kurt W. Kohn
Implemented by : Margot Sunshine
AKT is the cellular homolog of the retroviral oncogene v-Akt. The AKT family comprises three members (AKT1, AKT2 and AKT3), which, in general, are broadly expressed (Vivanco and Sawyers, 2002). AKT is activated by phosphatidylinositol 3-phosphate (PIP3), which is produced by PI(3)kinases (PI3K). As schematized in the MIM, PI3K heterodimers contain both a catalytic (p110) and a regulatory (p85) subunit. PI3K catalyses the phosphorylation of inositol lipids at the D3 position of the inositol ring (#4; B4). The resulting PIP3 activates a variety of downstream effectors, including AKT (#9; D4–5). For example, in response to survival factors such as hematopoietic growth factors (e.g., IL-3), AKT is recruited to the plasma membrane by its binding to PIP3, and is activated by sequential phosphorylation on Thr308 by PDK1 (phosphoinositide-dependent protein kinase-1) (#7; E4–5) and on Ser473 by PDK2 (#10; E4–5) or ILK (#15; E4–5) (Datta et al., 1999; Hill and Hemmings, 2002; Vivanco and Sawyers, 2002; Troussard et al., 2003).
AKT is negatively regulated by the lipid phosphatases PTEN (#20; B3), SHIP-1 and SHIP-2 (#21; B5), which prevent AKT activation by decreasing PIP3 levels (Damen et al., 1996; Stambolic et al., 1998; Wisniewski et al., 1999). Also, the protein phosphatase 2A (PP2A) inactivates AKT directly by dephosphorylating Ser473 and Thr308 (#19; E4 & F4); Ser473 being a better substrate than Thr308 (Andjelkovic et al., 1999). Carboxyl-terminal modulator protein (CTMP) binds to the carboxyl-terminal regulatory domain of AKT at the plasma membrane and reduces the activity of AKT by inhibiting phosphorylation on Ser473 and to a lesser extent Thr308 (#22; E5 & F5) (Maira et al., 2001). Conversely, HSP90 maintains the AKT activity by binding to AKT (#23; D3) and by preventing PP2A-dependent dephosphorylation of AKT (Sato et al., 2000). HSP90 also prevents proteasome-dependent degradation of PDK1 (#24; D2) (Fujita et al., 2002). AKT is therefore regulated by a complex network of phosphorylation/dephosphorylation reactions, which can be concisely summarized in the molecular interaction map.
