A recurring theme in neurobiology is the role of a set of molecules that support proliferation, differentiation and survival of neurons. These molecules, collectively referred to as neurotrophins, are essential for the development and maintenance of the vertebrate nervous system, mediating their signal into the cell by specific interaction with tyrosine kinase receptors of the TRK (Tyrosine Kinase Receptor) family. TRK family is composed of related transmembrane tyrosine receptor kinases that specifically bind neurotrophins: TRKA binds NGF (Nerve Growth Factor); TRKB binds BDNF (Brain Derived Neurotrophic Factor), NT3 (Neurotrophin-3) and NT4/5 (Neurotrophin-4/5); and TRKC binds NT3. Out of these, TRKA forms a high-affinity binding site for NGF, the best characterized[..]

Thrombin is a multifunctional serine protease involved in a number of pathophysiological processes that include blood clotting, inflammation, repair processes and tumor metastasis. In brain, thrombin regulates the viability of neurons and astrocytes by increasing survival under conditions of hypoglycemia and oxidative stress and inducing apoptosis under other conditions. Thrombin is also chemotactic for macrophages and mitogenic for smooth muscle cells, fibroblasts, and astrocytes and induces secretion of growth factors and cytokines from fibroblasts and smooth muscle cells. Most of the thrombin-mediated effects are preceded by morphological changes in cells that follow activation of PARs (Protease-Activated Receptors) (Ref.1).PARs are a unique class of heterotrimeric,[..]

The immune system recognizes the presence of pathogens by several proteins that bind to molecules secreted by the pathogen or carried on their surface. The cells responsible for these immune responses include the B-Cells, T-Cells, macrophages, neutrophils, basophils, eosinophils, endothelial cells, or mast cells (Ref.1). These cells have distinct roles in the immune system, and communicate with other immune cells by cytokines, which control proliferation, differentiation and function of cells of the immune system. Cytokines provide cells with the ability to communicate with one another and orchestrate complex multicellular behaviour. Cytokines play an important role in normal homeostatic tissue function and dysregulation of these cytokine networks is associated with[..]

The C (Complement) system consists of about twenty plasma proteins that function either as enzymes or as binding proteins. In addition to these plasma proteins, the complement system includes multiple distinct cell-surface receptors that exhibit specificity for the physiological fragments of complement proteins and that occur on inflammatory cells and cells of the immune system. Activation of the complement system initiates a series of enzymatic reactions in which the proteolytic cleavage and activation of successive complement proteins leads to the covalent bonding or fixing of complement fragments to the pathogen surface. A major consequence of this is the uptake and destruction of complement coated microbes by phagocytes that bear receptors for these complement[..]

Nuclear factor-kappaB (NF-kappaB) comprises a family of transcription factors that regulate the expression of genes encoding proteins and microRNAs (miRNA, miR) precursors and may regulate a variety of biological processes such as inflammation, immunity, cell proliferation, differentiation, survival, cancer development, and progression (Ref.1, 2 and 3). NF-kappaB is ubiquitously expressed and responds to diverse stimuli, including infectious agents, cytokines, or growth factors. NF-kappaB /Rel family include five members, namely RELA (p65), RELB, c-REL, p50, and p52, all comprising a conserved REL homology domain (RHD) near the N-terminus, which are able to form homo- or heterodimers with the ability to transmit receptor signals to the nucleus. Although NF-kappaB is[..]

p53 is a tumour suppressor protein that regulates the expression of a wide variety of genes involved in Apoptosis, Growth arrest, Inhibition of cell cycle progression, Differentiation and accelerated DNA repair or Senescence in response to Genotoxic or Cellular Stress. As a transcription factor, p53 is composed of an N-terminal Activation Domain, a central specific DNA Binding Domain, and a C-terminal Tetramerization Domain, followed by a Regulatory Domain rich in basic Amino acids. Having a short half-life, p53 is normally maintained at low levels in unstressed mammalian cells by continuous ubiquitylation and subsequent degradation by the 26S Proteasome. Nonphosphorylated p53 is ubiquitylated by the MDM2 (Mouse Double Minute-2) ubiquitin ligase. MDM2 binding[..]

Cell division is characterized by orchestrated events of chromosome segregation, distribution of cellular organelles, and the eventual partitioning and separation of the two daughter cells. Mitosis is a highly regulated process that assures the proper allotment of genetic material between each pair of daughter cells. It proceeds through successive stages of well-defined and coordinated sub-processes. Entry into mitosis is regulated by the CDC2 (Cell Division Cycle-2)/Cyclin-B heterodimer. CDC2/Cyclin-B activity drives the events of early mitosis, such as nuclear breakdown, chromosome condensation and spindle formation by phosphorylating cellular substrates. While CDC2 (the catalytic subunit of the heterodimer) is required to drive the events of early mitosis,[..]

Signals that derive from cell adhesion to the ECM (Extracellular Matrix) regulate important physiological events including cell motility and growth, and most often involve changes in the organization of the actin cytoskeleton. Cells interact with the ECM via transmembrane receptors, termed integrins, located at the cell surface. Binding of integrins to the ECM is accompanied by a localized clustering of these receptors, with the subsequent recruitment of structural and signaling molecules to the sites of matrix attachment, focal contacts, providing links to the actin cytoskeleton (Ref.1). Numerous proteins present at the cytoplasmic face of FA (Focal Adhesions) include cytoskeletal proteins such as vinculin and talin. In addition, numerous "signaling"[..]

P38s are a class of mitogen-activated protein kinases(MAPKs) are involved in cell differentiation, apoptosis and autophagy MAPKs are a family of Serine/threonine kinases that comprise 3 major subgroups, namely, ERK (Extracellular signal–Regulated Kinase), p38 MAPK and JNK (c-Jun N-terminal Kinases). Despite the diversity in function and upstream signaling events, MAPKs are always activated by a highly conserved mechanism that involves phosphorylation on both a Thr (Threonine) and a Tyr (Tyrosine) residue catalyzed by a MAPK kinase. The phosphorylation motif Thr-Xaa-Tyr is located in the activation loop or T loop whose amino acid sequence varies among different MAPK subfamilies. Accordingly, there are different activating MAPK Kinases that in most cases are[..]

Nonreceptor PTKs (Protein Tyrosine Kinases) are essential for the development and activation of B-Cells and T-Cells. The  Tec  kinases represent the second largest family of mammalian non-RTKs (Receptor Tyrosine Kinases), which are activated in blood cells by stimulation of Cytokine Receptors, Lymphocyte surface antigens, GPCR (G-Protein Coupled Receptors), receptor type PTKs, or Integrins (Ref.1).  Tec  family members include Tec,  BTK  (Bruton’s Tyrosine Kinase),  ITK  (IL-2-Inducible T-cell Kinase)/ EMT/TSK,  BMX  (Bone Marrow Kinase)/ETK (Epithelial and Endothelial Tyrosine Kinase) and  RLK  (Resting Lymphocyte Kinase)/TXK. Expression of most  Tec  kinases is restricted to hematopoietic[..]

Nuclear hormone receptors are transcription factors that bind DNA and regulate transcription in a ligand-dependent manner. PPARs (Peroxisome Proliferator-Activated Receptors) are ligand-inducible transcription factors that belong to the nuclear hormone receptor superfamily, together with the receptors for thyroid hormone, retinoids, steroid hormones and vitamin D that act as ligand-activated transcription factors. PPARs regulate gene expression by binding with RXR (Retinoid X Receptor) as a heterodimeric partner to specific DNA sequence elements termed PPRE (Peroxisome Proliferator Response Element) (Ref.1). This heterodimeric transcription factor complex then binds to cognate sequences in promoter regions of target genes involved in the catabolism of fatty acids. PPAR[..]

cAMP (Cyclic 3', 5'-Adenosine Monophosphate)-dependent Protein Kinase, commonly known as PKA (Protein Kinase-A), is a second messenger-dependent enzyme that has been implicated in a wide range of cellular processes, including transcription, metabolism, cell cycle progression and apoptosis. Known modulators of PKA activity include factors that either activate or inhibit AC (Adenylate Cyclase), resulting in an increase or decrease in cAMP levels. The enzyme occurs naturally as a four-membered structure with two regulatory (R) and two catalytic (C) subunits. Four genes encode the R subunits (RI-Alpha, RI-Beta, RII-Alpha and RII-Beta), and three encode the C subunits (C-Alpha, C-Beta and C-Gamma). Although there are major differences in the tissue distribution, biochemical[..]