The Akt Pathway, or PI3K-Akt Pathway is involved in fundamental cellular processes including protein synthesis, proliferation and survival. AKT also plays a regulatory role in angiogenesis and metabolism. The AKT pathway is activated by factors that induce PI3K which in turn activates mTOR pathways. The AKT signaling pathway plays an important regulatory role in many cellular survival pathways, primarily as an inhibitor of apoptosis. AKT signaling has been implicated in various cancers and is an active area of interest for anti-cancer therapeutics. The pathway can be activated by a range of signals, including hormones, growth factors and components of the extracellular matrix (ECM). PI3K can also be activated by G protein-coupled receptors (GPCR). Akt binds PIP3 through its pleckstrin homology (PH) domain, resulting in translocation of Akt to the membrane. PDK1, which is also brought to the membrane through its PH domain, phosphorylates Akt within its activation loop at Thr308. A second phosphorylation at Ser473 within the carboxy terminus is also required for activity and is carried out by the mTOR-rictor complex, mTORC2. AKT is activated by PI3K, which itself is activated by several upstream signaling pathways such as insulin receptors, receptor tyrosine kinases, G protein coupled receptors, cytokine receptors, etc. After activation, it targets several downstream molecules and change their activity by phosphorylation or complex formation. AKT is involved in cell proliferation, glucose metabolism, cell survival, cell cycle, protein synthesis, and in neuronal morphology and plasticity by regulation of several downstream molecules shown in this figure. AKT is involved in cell proliferation through interaction with a number of proteins involved in cell cycle Akt is also a key player in cardiovascular disease through its role in cardiac growth, angiogenesis, and hypertrophy. The pathway is highly regulated by multiple mechanisms, often involving cross-talk with other signalling pathways.
|Cytokine & Receptor Information|
Cytokines are a large group of proteins, peptides or glycoproteins that are secreted by specific cells of immune system. Cytokines are a category of signaling molecules that mediate and regulate immunity, inflammation and hematopoiesis. Cytokines are produced throughout the body by cells of diverse embryological origin. Cytokine is a general name; other names are defined based on their presumed function, cell of secretion, or target of action. For example, cytokines made by lymphocytes can also be referred to as lymphokines, while interleukins are made by one leukocyte and act on other leukocytes. And chemokines are cytokines with chemotactic activities.
Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action).
Several main groups of cytokines include: interleukins, chemokines, interferons, tumor necrosis factors (TNFs), colony-stimulating factors (CSFs), and TGF-beta superfamily members. Interleukins are a group of cytokines that were first seen to be expressed by leukocytes. They modulate inflammation and immunity by regulating growth, mobility and differentiation of lymphoid and other cells. Chemokines are chemotactic cytokines with the ability to induce directed chemotaxis in nearby responsive cells. Stimulated by pro-inflammatory cytokines infected tissues release chemokines, and chemokine gradients induce leukocytes to move between endothelial cells and pass the basement membrane into the infected tissues. Interferons are cytokines which are made and released by the cells of most vertebrates in response to the presence of pathogens (such as viruses, bacteria, or parasites, or tumor cells). Interferons play critical role in host defense mechanisms. The tumor necrosis factor (TNF) superfamily of cytokines act through ligand-mediated trimerization, causing recruitment of several intracellular adaptors to activate multiple signal transduction pathways for cell survival, death, and differentiation. Colony-stimulating factors (CSFs), also called haematopoietic growth factors, are secreted glycoproteins which regulate bone marrow production of circulating red and white cells, and platelets.
An important part of Cytokines’ action on the immune system is to stimulate immune cell proliferation and differentiation. Cytokines involved in this function include interleukin 1 (IL-1), which activates T cells; IL-2, which stimulates proliferation of antigen-activated T and B cells; IL-4, IL-5, and IL-6, which stimulate proliferation and differentiation of B cells; and other cytokines such as, interferon gamma, IL-3, IL-7 and colony-stimulating factor (GM-CSF).
Cytokines act on their target cells by binding specific membrane receptors. The receptors and their corresponding cytokines have been divided into several families based on their structure and activities. Type I cytokine receptors have certain conserved motifs in their extracellular amino-acid domain, and lack an intrinsic protein tyrosine kinase activity. Type II cytokine receptors are multimeric receptors composed of heterologous subunits, and are receptors mainly for interferons. The extracellular domains of type II cytokine receptors share structural similarities in their ligand-binding domain. Some cytokine receptors belong to the immunoglobulin superfamily, such as IL-1R alpha, IL-1R beta, IL-6R alpha, SCFR, c-kit, etc. Other cytokine receptors include TNF receptor family, chemokine receptors, and TGF-beta receptors.
Cytokines have been proved useful in immune-based therapies. For example, interferon-alpha, a cytokine with broad antiviral properties, has been proven to be useful in treating cancers, such as malignant melanoma. Cytokine therapy is not merely a tool of the future. In fact, several cytokine therapies are now routinely used by many people living with HIV.