Akt/SKG Substrate Peptide

Akt, also known as protein kinase B (PKB), is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration2. The Akt signaling pathway is activated by various types of cellular stimuli or toxic insults, leading to the phosphorylation and activation of Akt. This kinase is involved in a wide range of biological responses and is tightly regulated by phosphorylation events. Akt substrates include a variety of proteins that contribute to the regulation of cell survival, growth, and proliferation.

Akt functions by phosphorylating a range of substrates, which include metabolic enzymes, transcription factors, and other kinases. The phosphorylation of these substrates by Akt can either activate or inhibit their function, leading to the modulation of various cellular pathways. For instance, Akt phosphorylates the Ezrin-Radixin-Moesin-binding Phosphoprotein 50 (EBP50), which promotes the stability and mitogenic function of S-phase kinase-associated protein-2 (Skp2), thus facilitating cell proliferation1. The phosphorylation of EBP50 by Akt at threonine 156 allosterically enhances the binding of Skp2 to EBP50, which in turn regulates the localization and stability of Skp21.

Kinetic studies of the Akt family have revealed that all Akt isoforms follow a sequential kinetic mechanism, with ATP binding to the enzyme prior to the peptide substrate, suggesting that ATP is an initiating factor for Akt catalysis2. This ordered substrate addition mechanism is consistent across different Akt isoforms, although their kinetic parameters vary, with AKT2 and AKT3 showing the highest Km and kcat values, respectively2.

Medical Research and Cancer Therapy

Akt's role in cell proliferation and survival makes it a significant target in cancer research. Aberrant activation of Akt, often due to genetic mutations in the PTEN tumor suppressor or overexpression of receptor tyrosine kinases, is a hallmark of many cancers2. The development of pseudosubstrate peptides that inhibit Akt has shown potential in inducing cell growth inhibition, providing a prototype for peptide mimetic drugs that could be used in cancer therapy4.

Cardiovascular Research

In cardiovascular research, Akt has been implicated in the hypertrophic effects mediated by urocortin homologous peptides, which bind to CRFR2 receptors. These peptides, through the activation of the Akt pathway, lead to increased cell area, protein synthesis, and induction of natriuretic peptides, with Akt phosphorylation being crucial for their hypertrophic action3.

Metabolic Disorders

Akt is also central to the regulation of glucose uptake by mediating the translocation of glucose transporter 4 (GLUT4) to the plasma membrane in response to insulin. In skeletal muscle, insulin or contractile activity increases the phosphorylation of Akt substrate of 160 kDa (AS160), which is essential for GLUT4 translocation, suggesting a role for Akt in the treatment of metabolic disorders such as diabetes5.

Neuroscience

In the field of neuroscience, Akt has been found to control synaptic strength by phosphorylating the type A gamma-aminobutyric acid receptor (GABA(A)R), which is the principal receptor mediating fast inhibitory synaptic transmission in the brain. This phosphorylation increases the number of GABA(A)Rs on the plasma membrane surface, thereby enhancing synaptic transmission and contributing to synaptic plasticity6.