Ser473

Ser473 refers to the phosphorylated serine residue at position 473 in the human protein kinase B alpha (AKT1). It resides in the C-terminal hydrophobic motif of AKT1 and, together with phosphorylation of threonine 308, regulates kinase activity. In most cells, AKT is activated by growth factor signaling through PI3K, which leads to PDK1-mediated phosphorylation of Thr308 in the activation loop and mTOR complex 2 (mTORC2)–mediated phosphorylation of Ser473 in the hydrophobic motif. Phosphorylation at Ser473 promotes substrate access and maximal kinase activity, enabling phosphorylation of downstream targets involved in metabolism, growth, and survival. The corresponding serine residue in AKT2 and AKT3 is S474 and S472, respectively, and all share the same general regulatory mechanism.

Ser473 phosphorylation is commonly assessed as a surrogate marker of AKT pathway activation, detected by phospho-specific antibodies in Western blotting or immunohistochemistry. Phosphatases such as PHLPP1 and PHLPP2 can dephosphorylate Ser473, contributing to pathway inactivation.

Dysregulation of Ser473 phosphorylation has been reported in various diseases, most notably cancer and metabolic disorders. Elevated pS473 AKT is often associated with enhanced tumor growth, survival, and resistance to therapy, while reduced phosphorylation can reflect impaired insulin signaling. Therapeutic strategies sometimes aim to modulate mTORC2 activity or AKT Ser473 phosphorylation to influence AKT signaling.