GSK3 (Glycogen Synthase Kinase-3) is a ubiquitously expressed, highly conserved serine/threonine protein kinase found in all eukaryotes. Identified originally as a regulator of glycogen metabolism, GSK3 acts as a downstream regulatory switch for numerous signaling pathways, including cellular responses to WNT, Growth Factors, Insulin, RTK (Receptor Tyrosine Kinases), Hedgehog pathways, and GPCR (G-Protein-Coupled Receptors) and is involved in a wide range of signal transduction cascades involving cellular processes, ranging from glycogen metabolism, cell development, gene transcription, protein translation to cytoskeletal organization, cell cycle regulation, proliferation and apoptosis. Unlike most protein kinases involved in signaling, GSK3 is active in unstimulated,[..]

Angiogenesis, the growth of new blood vessels, plays a key role in many physiological and pathological processes, such as ovulation, embryogenesis, wound repair, inflammation, malignant tumor growth, retinopathies, rheumatoid arthritis, and angiogenesis-dependent diseases. One of the best-characterized modulators of angiogenesis is the heparin-binding FGF (Fibroblast Growth Factor) (Ref. 1).FGFs are a large family of multifunctional peptide growth factors of which there are at least 28 distinct members. The members of this peptide growth factor family have been identified in a variety of organisms and play pivotal roles in many cellular processes including mitogenesis, differentiation, migration, and cell survival During embryonic development, FGFs play a critical role[..]

Controlled cell proliferation is a predominant theme in normal embryonic and post-embryonic development, and, in many instances, cell-type specification and cell proliferation are intimately coupled. Several secreted intercellular signaling proteins that behave as morphogens during pattern formation are also implicated in the regulation of the cell cycle. Hedgehogs (Hhs) are one such class of morphogens that regulate an enormous variety of developmental events in the fly and vertebrate embryo and plays a central role in several cancers.The vertebrate Hh family is represented by at least three members: Dhh (Desert Hh), Ihh (Indian Hh) and Shh (Sonic Hh), two Patched homologs, Ptc1 (Patched-1) and Ptc2 (Patched-2); and three homologs of Ci (Cubitus interruptus, a 155 kDa[..]

PDGF (Platelet-derived growth factor) isoforms stimulate growth, survival and motility of mesenchymal cells and certain other cell types. They have important functions during embryonal development and in the control of tissue homeostasis in the adult. Overactivity of PDGF signaling is associated with the development of certain malignant diseases, as well as non-malignant diseases characterized by excessive cell proliferation. The PDGF isoforms are synthesized as precursor molecules with signal sequences, precursor sequences and growth factor domain. After dimerization, the isoforms are proteolytically processed to their active forms which bind to the receptors. The extracellular parts of the receptors contain 5 Ig-like domains; ligand binding occurs preferentially to[..]

TGF-Beta (Transforming Growth Factor-Beta) superfamily of secreted polypeptide growth factors play an important role in a variety of pathophysiologic processes, including angiogenesis, vascular remodeling, atherogenesis and in regulating cellular responses such as growth, proliferation, differentiation, migration, adhesion, survival, and specification of developmental fate. Apart from TGF-Beta, the superfamily also includes the Activins, NODAL and the BMPs (Bone Morphogenetic Proteins). These factors signal through heteromeric complexes of Type-II and Type-I serine-threonine kinase receptors, which activate the downstream SMAD (Sma and Mad Related Family) signal transduction pathway (Ref.1, 2 & 3).Based on their structures and known functional roles, the mammalian[..]

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[..]