Affecting millions of people every year, the fungal infection has become a worldwide health problem. Because of the undesirable side effects and limited repertoire of antifungal drugs, it is imminent to explore new antifungal drugs or discover novel potential targets for antifungal therapeutics. PI-3-kinases dependent signaling pathway has become an important target for antifungal drug discovery. Creative Biolabs has several years of experience in biological research and drug discovery, and now we have successfully developed an advanced antifungal drug discovery platform. Based on the PI-3-kinases dependent signaling pathway, we have explored a series of innovative and effective targets to favor our clients.
Introduction of the PI3K/Akt Signaling Pathway
The phosphoinositide 3-kinase (PI3K) pathway is widely involved in fundamental cellular processes, such as protein synthesis, metabolism, proliferation, as well as cell cycle progression and survival. As the key components of this pathway, PI3Ks and the downstream serine/threonine kinase Akt (also known as protein kinase B) regulate cellular activation, inflammatory responses, chemotaxis, and apoptosis. Dysregulation of the PI3K/Akt pathway is associated with numerous human diseases, including cancer, diabetes, cardiovascular disease, and neurological diseases. By linking multiple receptor classes to many essential cellular functions, this critical signal transduction system may be the most commonly activated signaling pathway and thus presents both an opportunity and a challenge for treatment of various diseases, including fungal infections.
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Fig.1 Structure of PI3K and Akt.
Composition of PI3K/Akt Signaling Pathway
There are five key components involved in this signaling pathway, namely receptor tyrosine kinase (RTKs), phosphatidylinositol 3-kinase (PI3K), phosphatidylinositol-4,5-bisphosphate (PIP2), phosphatidylinositol-3,4,5-bisphosphate (PIP3), and AKT (protein kinase B).
RTKs are the second major type of cell-surface receptors for many polypeptide growth factors, cytokines, and hormones. There are several ligands for RTKs, including nerve growth factor (NGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and insulin. Binding of a ligand to RTKs stimulates the receptor’s intrinsic protein-tyrosine kinase activity, which subsequently triggers a signal-transduction cascade leading to changes in cellular physiology and/or patterns of gene expression. RTKs are characterized by three functional domains: an extracellular ligand binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain.
PI3K is a lipid kinase which associates with activated protein tyrosine kinases, including growth factor receptors that are autophosphorylated on tyrosine residues in response to the binding of the specific ligands at the plasma membrane. Responsible for the phosphorylation of PtdIns at position D3 of the inositol ring, PI3K consists of two domains, a catalytic domain P110 and a regulatory domain P85. PI3K is directly activated by the binding of the regulatory subunit to the activated receptor. Additionally, adapter molecules such as the insulin receptor substrate (IRS) proteins, GTP binding RAS protein can also activate PI3K indirectly.
PIP2 and PIP3 are minor phospholipid components of cell membranes, which function in a remarkable number of crucial cellular processes. By binding to both PDK1 and AKT protein and recruiting AKT protein at the plasma membrane, PIP3 serves as the effector of multiple downstream targets of the PI3K pathway. PIP3 controls various processes at the plasma membrane, including phagocytosis, pinocytosis, regulated exocytosis, and cytoskeletal organization. PIP2 is involved in fundamental processes in membrane trafficking and plasma membrane-cytoskeleton linkages.
AKT, also known as protein kinase B, is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes, including glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. Once activated, AKT regulates a wide range of proteins involved in cell growth, proliferation, motility, and survival via phosphorylation activation or suppression.
Functions of the PI3K-Akt Signaling Pathway
PI3K-Akt pathway activation can induce the translocation of Akt from the plasma membrane to the cytoplasm and nucleus, where Akt regulates the activity of target proteins. There are many downstream effects of the PI3K-Akt pathway.
It has been well acknowledged that Akt can enhance cell growth through inhibition of TSC2 and indirectly activation of mTOR complex 1 (mTORC1), which is a critical regulator of translation initiation and ribosome biogenesis and plays an evolutionarily conserved role in cell growth and protein synthesis control.
By blocking the function of proapoptotic proteins and processes, the PI3K-Akt pathway can promote the survival of cells. Additionally, Akt can also inactivate the GSK3 to regulate the apoptosis and glucose metabolism via GSK3 phosphorylation.
The PI3K-Akt pathway is closely associated with cell proliferation by promoting the cell into the cell cycle to proliferation.
In addition to the above functions, the PI3K-Akt pathway is also involved in cell differentiation, motility, diabetes mellitus, learning and memory, cancer development, etc.
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Fig.2 Model of PI3K/AKT pathway. (Carnero, 2014)
Advantages of the PI3K-Akt Pathway Targets
PI-3-kinases dependent signaling pathway is one of our promising new targets for antifungal drug discovery. With state-of-the-art equipment and highly skilled and dedicated professionals, Creative Biolabs offers our valued clients one-stop custom-oriented services to meet your antifungal drug discovery research and development. We will be your best partner and facilitate the success of your projects. Please contact us for more information.
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