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[..]

MAPKs (Mitogen-Activated Protein Kinases) are Serine-threonine protein Kinases that are activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus. MAPKs are expressed in multiple cell types including Cardiomyocytes, Vascular Endothelial cells, and Vascular Smooth Muscle Cells. Three major MAPKs include ERKs (Extracellular signal-Regulated Kinases), JNKs (c-Jun NH(2)-terminal protein Kinases), and p38 Kinases. Members of the JNK/SAPK (Stress-Activated Protein Kinase) family of MAPKs are strongly stimulated by numerous Environmental Stresses, but also more modestly stimulated by Mitogens, Inflammatory Cytokines, Oncogenes, and inducers of Cell differentiation and morphogenesis. Ten mammalian JNK[..]

A number of inherited (constitutional/genetic) disorders are characterized by BM (Bone Marrow) failure usually in association with one or more somatic abnormality. The BM failure may involve all or a single lineage; in some cases it may be initially associated with a single peripheral cytopenia and then progress to pancytopenia. Scientifically, they constitute an exciting group of disorders and the two syndromes that are frequently associated with generalized BM failure? are FA (Fanconi’sAnemia, named for Swiss pediatrician, Guido Fanconi) and DC (DyskeratosisCongenita) (Ref.1). FA is a rare autosomal recessive chromosome instability disorder clinically characterized by developmental defects, progressive BM failure, progressive AA (Aplastic Anemia), diverse[..]

Proliferation and migration of VSMCs (Vascular Smooth Muscle Cells) in arteries plays an important role in the pathophysiology of atherosclerosis, hypertension, and restenosis after angioplasty. A wide variety of growth factors, cytokines, and hormones activate these responses in blood vessels. A prominent growth factor for VSMCs is Angiotensin (Angiotensin-I and II), the main peptide of the Renin Angiotensin System. Renin is an aspartyl protease that catalyzes the first step in the activation of the RAS. Active renin specifically cleaves the 10 amino acids from the N-terminus of Agt to form Ang I. In humans, there is an excess of Agt in serum. Likewise, ACE is ubiquitous in the endothelium and plasma.The primary source of renin in the circulation is the kidney, where[..]

Rho is a member of the Ras superfamily of small GTP-binding proteins that play a central role in diverse biological processes such as Actin cytoskeleton organization, Microtubule dynamics, Gene transcription, Oncogenic transformation, Cell cycle progression, Adhesion and Epithelial wound repair. To date, 20 genes encoding different members of the Rho family have been identified in the human genome, and each one acts as a molecular switch to control distinct biochemical pathways. The mammalian Rho GTPase family currently consists of three subfamilies, Rho (RhoA, RhoB and RhoC), Rac (Rac1, Rac2 and Rac3) and CDC42 (Cell Division Cycle-42) (CDC42Hs and G25K). Rho proteins cycle between an active GTP-bound state and an inactive GDP-bound state. Their activation state is[..]

MAPKs are a group of protein Serine/threonine Kinases that are activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus. In combination with several other signaling pathways, they can differentially alter phosphorylation status of numerous proteins, including Transcription Factors, Cytoskeletal proteins, Kinases and other Enzymes, and greatly influence Gene Expression, Metabolism, Cell Division, Cell Morphology and Cell Survival. Furthermore, epigenetic aberrations of these enzymes or of the signaling cascades that regulate them have been implicated in a variety of human diseases including Cancer, Inflammation and Cardiovascular disease. There are four major groups of MAPKs in mammalian[..]

mTOR (Mammalian Target of Rapamycin) is a 289-kDa serine/threonine protein kinase and a member of the PIKK (Phosphatidylinositol 3-Kinase-related Kinase) family. The protein consists of a Catalytic Kinase domain, an FRB (FKBP12–Rapamycin Binding) domain, a putative Auto-inhibitory domain (Repressor domain) near the C-terminus and up to 20 tandemly repeated HEAT motifs at the Amino terminus, as well as FAT (FRAP-ATM-TRRAP) and FATC (FAT C-terminus) domains. The C-terminus of TOR is highly homologous to the catalytic domain of PI3K (Phosphatidylinositol 3-Kinase). mTOR proteins are evolutionarily conserved from yeast to human in the C-domain, with human, mouse, and rat mTOR proteins sharing 95% identity at the amino acid level. The human mTOR gene encodes a protein[..]

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[..]

IL-2 (Interleukin-2) is a T-Cell-derived cytokine important in the regulation of growth and differentiation of T-Cells, B-Cells, natural killer cells, glioma cells, and cells of the monocyte lineage after specifically interacting with its receptors. Human IL-2 is a 133-amino acid polypeptide with a molecular mass of 15-18 kDa. IL-2 signaling is mediated by a multichain receptor complex consisting of an alpha (CD25), beta (CD122) and gamma (CD132) chain. The IL-2R (IL-2 Receptor) alpha subunit primarily increases the affinity of ligand binding and is not known to contain a signaling domain, whereas the beta and gamma subunits participate in both ligand binding and signal transduction. The IL-2R signaling system proceeds through at least three different pathways, which[..]

Fas (also called Apo1 or CD95) is a death domain-containing member of the TNFR (Tumor Necrosis Factor Receptor) superfamily. It has a central role in the physiological regulation of Programmed Cell Death and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. Although the FasL (Fas Ligand)-Fas system has been appreciated mainly with respect to its death-inducing function, it also transduces proliferative and activating signals through pathways that are still poorly defined. The Fas Receptor induces an apoptotic signal by binding to FasL expressed on the surface of other cells. Fas is a Type-I transmembrane protein, where as FasL a Type-II Transmembrane protein of TNF family and can be shed in a soluble form by action of[..]

STATs (Signal Transducers and Activators of Transcription) are a family of cytoplasmic proteins with SH2 (Src Homology-2) domains that act as signal messengers and transcription factors that mediate many aspects of cellular immunity, proliferation, apoptosis and differentiation. The STAT family comprises seven members namely, STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6. They range in size from 750 to 850 amino acids and the entire STAT family can be divided into two groups based on their functions. The first group consists of STAT2, STAT4, and STAT6, which are activated through a small number of cytokines and are involved in T-cell development and IFN-γ signaling. The second group includes STAT1, STAT3, and STAT5, which are activated in different[..]

The G12 subfamily of heterotrimeric G proteins, comprised of the Alpha-subunits G-Alpha12 and G-Alpha13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal changes to cell growth and oncogenesis. Activated G-Alpha12 and G-Alpha13 have a molecular weight of 43,000 kDa and they show more than 66% amino acid identity. They stimulate mitogenic signaling pathways leading to the oncogenic transformation of fibroblast cell lines. Recent analyses have indicated that G-Alpha12 and G-Alpha13 regulate cytoplasmic as well as nuclear signaling events through downstream targets such as Ras-, Rac-, Rho-, and CDC42 (Cell Division Cycle-42) dependent pathways, leading to cytoskeletal reorganization and to the activation of MAPK[..]