Proline-rich AKT1 substrate 1 (PRAS40) (PRAS40)

Proline-rich AKT1 substrate 1 (PRAS40), also known as AKT1S1, is a 40 kDa protein that acts as a crucial negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1). In its basal, unphosphorylated state, PRAS40 binds to the Raptor subunit of mTORC1, effectively blocking the recruitment of substrates and inhibiting the complex's kinase activity (UniProt: Q96B36). Upon activation of the PI3K/AKT pathway by insulin or growth factors, AKT phosphorylates PRAS40 at Threonine 246, which facilitates subsequent phosphorylation at Serine 183 by mTORC1 itself (PubMed: 17397850). These phosphorylation events trigger the dissociation of PRAS40 from mTORC1 and its sequestration by 14-3-3 proteins, thereby activating mTORC1 to promote protein synthesis and cell growth. PRAS40 is frequently overexpressed or hyperphosphorylated in various malignancies, including breast, prostate, and liver cancers, making it a key node in oncogenic signaling (PubMed: 25132269). While direct PRAS40 inhibitors are not yet in clinical use, the phosphorylation status of PRAS40 serves as a vital pharmacodynamic biomarker for evaluating the efficacy of AKT and mTOR inhibitors in clinical trials (PubMed: 21873570).

Other names

AKT1S1Proline-rich AKT substrate of 40 kDaLobe

Inhibition of upstream kinases (AKT or mTOR) prevents the phosphorylation of PRAS40, thereby maintaining its inhibitory association with mTORC1 and suppressing downstream anabolic signaling (PubMed: 17397850).