AKT1
AKT1 (protein kinase B α) is a serine/threonine kinase that integrates insulin and growth-factor signals into commands for metabolism, proliferation, and survival.
Function
PI3K converts the membrane lipid PIP2 to PIP3; AKT docks at PIP3 through its PH domain and is activated by phosphorylation at two sites (Thr308 by PDK1, Ser473 by mTORC2). Active AKT then phosphorylates a broad substrate set with a shared theme: keep the cell alive and growing. It inactivates the pro-apoptotic proteins BAD and FOXO, drives protein synthesis by inhibiting TSC2 and thereby activating mTOR, and moves glucose transporters to the membrane in response to insulin. PTEN opposes the whole route by dephosphorylating PIP3.
In cancer
AKT1 carries the E17K activating mutation in a few percent of breast, colorectal, and ovarian cancers, and AKT1 amplification recurs in gastric cancers. More often, AKT is hyperactivated indirectly — through PIK3CA mutation or PTEN loss. AKT inhibitors have struggled in the clinic for toxicity reasons: the same pathway manages normal glucose homeostasis, so inhibition produces hyperglycemia and rash.
Notes
- Human gene symbol: AKT1; UniProt P31749; 480 amino acids; AGC kinase family; three isoforms (AKT1/2/3) with partially overlapping roles.