Engagement of integrin receptors with extracellular ligands gives rise to the formation of complex multi-protein structures that link the ECM (Extracellular Matrix) to the cytoplasmic actin cytoskeleton and signaling proteins including Talin, Alpha-actinin, Vinculin, Zyxin, Paxillin and FAK (Focal Adhesion Kinase). These adhesive complexes are dynamic, often heterogeneous structures, varying in size and organization, and signaling through these complexes and focal adhesions have been implicated in the regulation of a number of key cellular processes, including growth factor induced mitogenic signals, cell survival, cell proliferation and migration, cell locomotion and regulation of cell cycle (Ref.1). FAK is a non-receptor cytosolic PTK with a central catalytic[..]
Interleukin-22 (IL-22) is a member of the IL-10 related cytokine family which includes IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26. It is generally secreted by Th17 and Th22 cells. Other immune cells like mast cells, NKT cells, natural killer22 (NK22) cells, lymphoid tissue inducer (LTi) and LTi-like cells also produce IL22. It exerts its effect on non-hematopoietic stromal cells including epithelial cells, keratinocytes, and hepatocytes.IL-22 is important for the host defense against extracellular pathogens, at mucosal surfaces as well as in tissue repair and wound healing (Ref. 1 and 2). IL 22 signals through a type 2 cytokine receptor that comprised of a heterodimeric complex of IL22RA1 and IL-10R2 (IL-10Rb). A soluble IL-22R called IL-22-binding protein[..]
IL4 is a multifunctional cytokine produced by TH2 type helper T cells, fibroblasts, mast cells, basophils, eosinophils, adipose, and a wide range of epithelial cells. IL4 acts on a broad range of cells, including keratinocytes, in which it induces IL6 production. IL4 cognate receptors are of two types: I IL4R (IL4RI) and type II IL4R (IL4RII). IL4RI are mostly present on immune cells and forms heterodimer with the common gamma-chain subunits. IL4RII on the other hand is found on the surface of non-hematopoietic cells and is composed of IL4Ralpha and the IL13Ralpha1 subunits. IL4 activates tyrosine kinases JAK1/3 and TYK2, which are recruited on the transmembrane domain of IL4RII and mediate its phosphorylation, leading to the activation of PI3K/AKT, MAPK,[..]
CTLs (Cytotoxic T Lymphocytes) and NK (Natural Killer) cells are the key immune effectors that eradicate infected cells or tumors. To destroy these targets, CTLs and NK cells mostly use the granule exocytosis pathway, which releases perforin and Granzymes from cytolytic granules into the immunological synapse formed with the target. Granzyme-A and Granzyme-B, the most abundant Granzymes, are delivered to the target cell cytosol through perforin and independently induce cell death. Granzyme-B enters the target-cell cytosol by a poorly understood mechanism involving perforin. Granzyme-B induces apoptosis through Caspase-dependent and Caspase-independent mechanisms (Ref.1). Granzyme-B is unique among serine proteases because, like cysteine protease Caspases, it[..]
IL6 (Interleukin-6) is a pleiotropic cytokine that not only affects the immune system, but also acts in other biological systems and many physiological events in various organs including the inflammation, hematopoiesis, and oncogenesis by regulating cell growth, gene activation, proliferation, survival, and differentiation. This protein signals through a receptor composed of two different subunits, an alpha subunit that produces ligand specificity and GP (Glycoprotein) 130, a receptor subunit shared in common with other cytokines in the IL-6 family. Binding of IL6 to its receptor initiates cellular events including activation of JAK (Janus Kinase) kinases and activation of RAS-mediated signaling. Activated JAK kinases phosphorylate and activate STAT transcription[..]
IL9 (Interleukin-9) is a pleiotropic cytokine secreted by activated T cells, mainly TH2 and TH9. Other cells like mast cells, Treg cells and TH17, innate lymphoid cells, NKT cells, and dendritic cells can also secrete IL9. IL9 generally play an important role in immune response, its major target include T-cell clones, hematopoietic progenitors, mast cells, B lymphocytes and immature neuronal cell lines. In addition, it may be involved in tumorigenesis (Ref.1). IL9 is a member of the four-helix cytokine family that signals through the the two chain IL9 receptor that include the IL9RA (IL9–specific alpha chain) and the common gamma chain, that is shared by IL-2, IL-4, IL-7, IL-15 and IL-21 receptors. IL9R is expressed in membrane-bound and soluble[..]
Insulin is the major hormone controlling critical energy functions such as glucose and lipid metabolism. Insulin elicits a diverse array of biological responses by binding to its specific receptor. The insulin receptor belongs to a subfamily of receptor tyrosine kinases that includes the IGF (Insulin-like Growth Factor) receptor and the IRR (Insulin Receptor-Related Receptor). These receptors are tetrameric proteins consisting of two alpha and two beta subunits that function as allosteric enzymes in which the alpha subunit inhibits the tyrosine kinase activity of the beta subunit. Insulin has diverse effects on cells including stimulation of glucose transport, gene expression and alterations of cell morphology. The hormone mediates these effects by activation of[..]
The complement system refers to a series of proteins circulating in the blood and bathing the fluids surrounding tissues. The proteins circulate in an inactive form, but in response to the recognition of molecular components of microorganism, they become sequentially activated, working in a cascade where in the binding of one protein promotes the binding of the next protein in the cascade. There are 3 complement pathways that make up the complement system: the classical complement pathway, the lectin pathway, and the alternative complement pathway. The pathways differ in the manner in which they are activated and ultimately produce a key enzyme called C3 convertase .The alternative complement pathway constitutes the humoral component of natural defence against[..]
Signaling pathways mediating the transduction of information between cells are essential for development, cellular differentiation and homeostasis. Their dysregulation is also frequently associated with human malignancies. The JAK (Janus tyrosine Kinase)-STAT (Signal Transducer and Activator of Transcription) pathway represents one such signaling cascade whose evolutionarily conserved roles include cell proliferation and haematopoiesis. JAK belongs to a family of non-receptor protein tyrosine kinases of approximately 130 kDa, comprising of JAK1, JAK2, JAK3 and TYK2 (non-receptor Protein Tyrosine Kinase-2). STATs are latent cytoplasmic transcription factors that become activated after recruitment to an activated receptor complex. Seven STAT proteins have been[..]
IL-1 (Interleukin-1) is a proinflammatory cytokine that stimulates a broad spectrum of immune and inflammatory responses. IL-1 is produced by activated macrophages, endothelia cells, B-Cells, and fibroblast cells. It induces inflammatory responses, edema, promotes the production of Prostaglandins, IL-2, and the growth of leukocytes (Ref.1). There are two forms of IL-1 encoded by distinct genes, IL-1 Alpha and IL-1 Beta. IL-1 Beta is produced as a 269 amino acid precursor that is cleaved by ICE (IL-1Beta Converting Enzyme) to the active IL-1 Beta form that is secreted. IL-1 induces cellular response through two subunits of its receptor, IL-1R1 (IL-1 Receptor1) and IL-1RAcP (IL-1 Receptor Accessory Protein). When it binds to its cell-surface receptor, IL-1 initiates a[..]
Throughout adult life, all blood cells are constantly regenerated from a small pool of hematopoietic stem cells. A single purified stem cell injected into a lethally irradiated host is sufficient to reconstitute all lineages, demonstrating pluripotency and an enormous regenerative potential. Genes encoding secreted growth factors, signal transduction molecules and nuclear proteins regulate this process. The helical cytokine family comprises structurally related secreted proteins that play an important role as hematopoietic growth factors. Their cognate receptors are single transmembrane proteins that constitute the so-called cytokine receptor superfamily. One such ligand-receptor pair is TPO (Thrombopoietin), also known as the c-MPL ligand or MGDF (Megakaryocyte Growth[..]
The lymphocyte population is mainly made up of the T-lymphocytes (Thymus-Derived Lymphocytes), B-lymphocytes (bone-marrow-derived), and the NK cells (Natural-Killer Cells). T-lymphocytes mediating the cellular immunity, along with B lymphocytes mediating humoral immunity, provide adaptive immunity, which work in close collaboration with the innate immune system. B-lymphocytes mature in the bone marrow itself, while the T-lymphocytes require the thymus to mature, before being deployed to the peripheral lymphoid organs for further antigen-mediated differentiation. These cells are responsible for antibody production, direct cell-mediated killing of virus-infected and tumor cells, and regulation of the immune response (Ref.1).T cells are key mediators of the adaptive[..]
