RAC-gamma serine, threonine-protein kinase(AKT3)

Description of RAC-gamma serine/threonine-protein kinase(AKT3)

Introduction

RAC-gamma serine/threonine-protein kinase, also known as AKT3, is a member of the AKT family of serine/threonine kinases. It plays a crucial role in cell survival, proliferation, and metabolism, making it an attractive target for drug development. In this article, we will discuss the structure, activity, and potential applications of AKT3 as a drug target.

Structure of AKT3

AKT3 is a 479 amino acid protein that belongs to the AGC (protein kinase A, G, and C) subfamily of serine/threonine kinases. It consists of three main domains: an N-terminal pleckstrin homology (PH) domain, a central catalytic domain, and a C-terminal regulatory domain. The PH domain is responsible for binding to phospholipids, while the catalytic domain is responsible for the kinase activity. The regulatory domain contains a hydrophobic motif (HM) that is crucial for the activation of AKT3.

Activity of this protein

AKT3 is activated by phosphorylation at two key residues, Thr308 and Ser473, by upstream kinases. The phosphorylation at Thr308 is catalyzed by phosphoinositide-dependent kinase 1 (PDK1), while the phosphorylation at Ser473 is catalyzed by the mammalian target of rapamycin complex 2 (mTORC2). Once activated, AKT3 phosphorylates a wide range of downstream substrates, including transcription factors, metabolic enzymes, and cell cycle regulators.

One of the key functions of AKT3 is to promote cell survival by inhibiting apoptosis. It does so by phosphorylating and inactivating pro-apoptotic proteins, such as Bad and caspase-9. AKT3 also plays a crucial role in cell proliferation by promoting the activation of the mTOR signaling pathway, which is essential for protein synthesis and cell growth. Additionally, AKT3 is involved in glucose metabolism, lipid metabolism, and cell migration.

Application of AKT3 as a Drug Target

Due to its role in cell survival, proliferation, and metabolism, AKT3 has been identified as a potential drug target for various diseases, including cancer, diabetes, and neurodegenerative disorders.

Cancer

AKT3 is frequently overexpressed in various cancers, and its activity is associated with tumor growth, invasion, and metastasis. Inhibiting AKT3 activity has been shown to suppress the growth of cancer cells and sensitize them to chemotherapy. Several AKT3 inhibitors are currently in clinical trials for the treatment of various cancers, including breast, lung, and prostate cancer.

Diabetes

AKT3 plays a crucial role in glucose metabolism by promoting the translocation of glucose transporter 4 (GLUT4) to the cell membrane, which facilitates glucose uptake. In diabetes, this process is impaired, leading to high blood glucose levels. Targeting AKT3 could potentially improve glucose metabolism and help manage diabetes. In fact, a recent study showed that inhibiting AKT3 activity improved insulin sensitivity in obese mice.

Neurodegenerative Disorders

AKT3 has also been implicated in the pathogenesis of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. It has been shown to regulate the activity of key proteins involved in the formation of abnormal protein aggregates, a hallmark of these diseases. Targeting AKT3 could potentially prevent the formation of these aggregates and slow down the progression of neurodegeneration.

Conclusion

In summary, AKT3 is a serine/threonine-protein kinase that plays a crucial role in cell survival, proliferation, and metabolism. Its dysregulation has been linked to various diseases, making it an attractive drug target.