The Chemokine receptor CXCR4 is a 352 amino acid rhodopsin-like GPCR and selectively binds the CXC chemokine Stromal Cell-Derived Factor 1 (SDF1) also known as CXCL12. Classically, two alternatively spliced isoforms of SDF have been identified. SDF1Alpha is an 89 amino acid protein that is the predominantly expressed form of SDF1 while SDF1Beta contains a four amino acid extension at the carboxyl terminus. Recently, an additional four splice variants that contain 30 (SDF1Gamma), 31 (SDF1Delta), 1 (SDF1Epsilon), and 51 (SDF1phi) amino acid extensions at the carboxyl terminus compared to SDF1Alpha have been identified (Ref.1).CXCL12 is the sole ligand for the chemokine receptor CXCR4.This receptor has been described as undergoing dimerization after binding to CXCL12 or[..]

Adhesive interactions between cells and ECM (Extracellular Matrix) proteins play a vital role in biological processes, including cell survival, growth, differentiation, migration, inflammatory responses, platelet aggregation, tissue repair and tumor invasion and perturbing this coordination can lead to events such as malignant transformation. The major groups of proteins mediating these interactions are a family of cell surface receptors known as Integrins, named for their role in integrating the intracellular cytoskeleton with the ECM (Ref.4). The signals from these adhesion receptors are integrated with those originating from growth factor receptors in order to organize the cytoskeleton, stimulate cell proliferation and rescue cells from matrix detachment and[..]

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[..]

One of the most fundamental issues in current biology is how to maintain the critical balance between cell survival and death, both during development and in adulthood. Unrestrained cell division and survival leads to various forms of tumor, while excessive or premature cell death may lead to a variety of diseases such as Alzheimer's, Parkinson's and Multiple Sclerosis. In the nervous system, a family of Neurotrophins, which includes NGF (Nerve Growth Factor), BDNF (Brain Derived Neurotrophic Factor), NT3 (Neurotrophin3) and NT4/5 (Neurotrophin-4/5), maintains this critical balance of cell survival and death. The best characterized of these is the NGF, a neurotrophic protein which is important for the growth and survival of diverse peripheral and central[..]

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[..]

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[..]

The Notch signaling pathway is a fundamental signaling system used by neighboring cells to communicate with each other in order to assume their proper developmental role. Notch proteins are cell surface transmembrane-spanning receptors which mediate critically important cellular functions through direct cell-cell contact. Interaction between Notch and its proposed ligands initiates a signaling cascade that governs cell fate decisions such as differentiation, proliferation, and apoptosis in numerous tissue types. The core elements of the Notch signaling system include the Notch receptor, DSL ligands (Delta and Serrate/Jagged in Drosophila and vertebrates, Lag2 in Caenorhabditis elegans) and CSL DNA-binding proteins (CBF1/RBPJ-kappa in vertebrates, Su(H) [Suppressor of[..]

Oncostatin M (OSM) is a 28-kDa pleiotropic cytokine belonging to the Interleukin-6 (IL-6)familythat bears closest homology toleukemia inhibitory factor (LIF). Human OSM (hOSM) is a252 amino acid precursor polypeptide that is mainly expressed by neutrophils, activated macrophages, dendritic cells and T-cells. OSM appears to play important role in diverse biological processes like development of blood cells, differentiation, inflammation, growth, metabolism and neuroprotection. OSM signals through heterodimers of transmembrane receptor GP130 with either leukemia inhibitory factor receptor (LIFR) or oncostatin M receptor (OSMR). After recruiting therequired receptors, OSM signals through JAK/STAT, MAPK and PI3K/AKT pathways (Ref.1 and 2).JAK/STAT pathway is the major[..]

Bone remodeling and homeostasis is an essential function that regulates skeletal integrity throughout adult life in higher vertebrates and mammals. The structural and metabolic integrity of bone is maintained through the dynamic process of bone remodeling that results from the coordinate action of bone resorption by osteoclasts and the formation of new bone by osteoblasts. Regulation of bone remodeling occurs through multiple mechanisms that ultimately converge on the interaction of osteoclasts or their precursors with osteoblasts and bone marrow stromal cells. Key factors supplied by the stromal environment are cytokines such as IL1, IL11, IL17, CSF1 (Colony Stimulating Factor-1) and the TNF receptor ligand family, RANKL (Receptor Activator of NF-kappaB Ligand; also[..]

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[..]

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[..]