AKT1S1 - Proline-rich AKT1 substrate 1 | Elisa - Clia - Antibody - Protein

Background:

AKT1S1, also known as proline-rich AKT1 substrate 1 or PRAS40, is a protein that acts as a substrate for AKT1 (Protein Kinase B, isoform 1). It plays a crucial role in regulating the mTOR (mechanistic target of rapamycin) signaling pathway, which is involved in controlling cell growth, proliferation, and survival. AKT1S1 contains proline-rich motifs that serve as docking sites for protein-protein interactions. When phosphorylated by AKT1 at specific sites, such as Serine 183, AKT1S1 dissociates from mTORC1 (mTOR Complex 1), leading to activation of mTORC1 and subsequent stimulation of protein synthesis and cell growth.The regulation of AKT1S1 by AKT1 and its involvement in mTOR signaling make it a key player in cellular processes such as cell growth, proliferation, and metabolism. Dysregulation of this pathway can contribute to various diseases, including cancer and metabolic disorders. Therefore, understanding the function of AKT1S1 and its interactions with AKT1 and mTOR is important for elucidating disease mechanisms and developing potential therapeutic strategies.

Protein Structure:

• N-Terminal Proline-Rich Domain: Contains sequences that are rich in proline residues, which are important for protein-protein interactions.
• C-Terminal Ser/Thr-Rich Region: This region includes multiple serine and threonine residues that are potential phosphorylation sites.
• Phosphorylation Sites:
• Thr246: A major phosphorylation site for AKT1, crucial for regulating AKT1S1’s function and interaction with other proteins.
• Additional Sites: Other potential phosphorylation sites may be targeted by different kinases, influencing AKT1S1’s activity and interactions.

Classification and Subtypes:

• Family: AKT1S1 is part of the larger family of proteins involved in the AKT signaling pathway.
• Subtypes: AKT1S1 does not have subtypes but interacts with multiple proteins in various signaling pathways.

Function and Biological Significance:

• mTORC1 Regulation: AKT1S1 is a key component of the mTORC1 (mechanistic target of rapamycin complex 1) signaling pathway. Phosphorylation by AKT1 leads to its dissociation from mTORC1, relieving inhibition and allowing mTORC1 activation.
• Cell Growth and Survival: By regulating mTORC1, AKT1S1 plays a vital role in promoting cell growth and survival, especially under nutrient-rich conditions.
• Glucose Metabolism: AKT1S1 influences glucose metabolism by modulating insulin signaling and glucose uptake.
• Protein Synthesis: Through mTORC1, AKT1S1 affects protein synthesis, cell proliferation, and overall cellular growth.

Interactions:

• Upstream Regulators: AKT1 is a primary upstream kinase that phosphorylates and regulates AKT1S1.
• mTORC1 Complex: AKT1S1 directly interacts with components of the mTORC1 complex, including mTOR and RAPTOR, to regulate its activity.
• 14-3-3 Proteins: Phosphorylated AKT1S1 binds to 14-3-3 proteins, which sequester it in the cytoplasm and prevent its association with mTORC1.

Clinical Issues:

• Cancer: Dysregulation of the AKT1/AKT1S1/mTORC1 pathway is commonly observed in various cancers, contributing to uncontrolled cell growth and survival. Mutations or altered expression of AKT1S1 can lead to aberrant activation of mTORC1.
• Metabolic Disorders: AKT1S1 plays a role in insulin signaling, and its dysregulation can contribute to insulin resistance and type 2 diabetes.
• Neurodegenerative Diseases: Abnormal AKT1S1 signaling is implicated in neurodegenerative diseases, where it affects neuronal survival and metabolism.

Summary:

AKT1S1 (PRAS40) is a critical regulator of the mTORC1 pathway, influencing cell growth, survival, and metabolism. It is phosphorylated by AKT1, which controls its interaction with the mTORC1 complex and other proteins. Dysregulation of AKT1S1 is associated with various diseases, including cancer, metabolic disorders, and neurodegenerative conditions. Understanding the role of AKT1S1 in these pathways provides insight into potential therapeutic targets for these diseases.