AKT1S1 phospho T246
Domain
The TOS motif mediates interaction with RPTOR, leading to promote phosphorylation by mTORC1 complex.
Function
Negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1), an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth (PubMed:17277771, PubMed:17386266, PubMed:17510057, PubMed:29236692). In absence of insulin and nutrients, AKT1S1 associates with the mTORC1 complex and directly inhibits mTORC1 activity by blocking the MTOR substrate-recruitment site (PubMed:29236692). In response to insulin and nutrients, AKT1S1 dissociates from mTORC1 (PubMed:17386266, PubMed:18372248). Its activity is dependent on its phosphorylation state and binding to 14-3-3 (PubMed:16174443, PubMed:18372248). May also play a role in nerve growth factor-mediated neuroprotection (By similarity).
Post-translational modifications
Phosphorylated by AKT1; phosphorylation takes place in response to insulin treatment and promotes AKT1S1 interaction with 14-3-3 proteins, leading to relieve its inhibitor activity (PubMed:12524439, PubMed:17386266). Phosphorylated by MTOR following mTORC1 activation, inhibiting AKT1S1 inhibitor activity: phosphorylation by MTOR probably serves as a feedback loop that relieves inhibition from AKT1S1 in response to mTORC1 inactivation (PubMed:17517883). Phosphorylation at Thr-246 by DYRK3 relieves inhibitory function on mTORC1 (PubMed:23415227).
Tissue Specificity
Widely expressed with highest levels of expression in liver and heart. Expressed at higher levels in cancer cell lines (e.g. A-549 and HeLa) than in normal cell lines (e.g. HEK293).
Cellular localization
- Cytoplasm
- Cytosol
- Found in the cytosolic fraction of the brain.
Alternative names
PRAS40, AKT1S1, Proline-rich AKT1 substrate 1, 40 kDa proline-rich AKT substrate