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[..]

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[..]

Unlimited replicative potential and widespread genomic disarray are among the most common characteristics exhibited by human cancer cells. Although several distinct molecular pathways regulate specific aspects of each of these phenotypes, specialized chromosomal terminal structures, termed telomeres act as essential regulators of both cell life span and chromosomal integrity (Ref.1).Telomeres are dynamic DNA-protein complexes that cap the ends of linear chromosomes, preventing detrimental chromosome rearrangements and defending against genomic instability and the associated risk of cancer. Telomeres shorten every time a cell divides because of incomplete DNA replication and DNA end processing. When telomere length reaches a critical point, cells stop dividing and[..]

BRCA1(Breast Cancer Susceptibility Protein-1) is a versatile protein that links DNA damage sensing and DDR effectors. BRCA1 interacts with tumour suppressors, DNA repair proteins and cell cycle regulators through its various functional domains and thereby has diverse roles in multiple DNA repair pathways (particularly HR, NHEJ and SSA (single-strand annealing)) and in checkpoint regulation. BRCA1 contains an amino-terminal RING domain that has E3 ubiquitin ligase activity (which catalyses protein ubiquitylation) and a BRCT(BRCA1 C-Terminal) domain that facilitates phospho-protein binding.BASC (BRCA1-Associated Genome Surveillance Complex), a super complex of BRCA1, is key to recognizing and repairing DNA damage. This complex includes tumor suppressors and DNA damage[..]

The extended growth potential of cancer cells is critically dependent upon the maintenance of functional telomeres, which are specialized chromosomal DNA-protein structures in the terminal regions of eukaryotic chromosomes (Ref.1). In order to divide, a normal cell has to replicate the entire DNA in its chromosomes. But normal cells have difficulty in copying the last few bases on the telomere. As a result, the telomere shortens with each round of DNA replication and cell division and as a cell ages, the telomere keeps shortening until it reaches a finite length. At that point cells stop dividing and this halt in growth is triggered by a gene p53 that is activated in response to DNA damage. A telomere that becomes too short no longer protects the chromosome from DNA[..]

Progress in the eukaryotic cell cycle is driven by oscillations in the activities of CDKs (Cyclin-Dependent Kinases). CDK activity is controlled by periodic synthesis and degradation of positive regulatory subunits, Cyclins, as well as by fluctuations in levels of negative regulators, by CKIs (CDK Inhibitors), and by reversible phosphorylation. The mammalian cell cycle consists of four discrete phases: S-phase, in which DNA is replicated; M-phase, in which the chromosomes are separated over two new nuclei in the process of mitosis. These two phases are separated by two so called “Gap” phases, G1 and G2, in which the cell prepares for the upcoming events of S and M, respectively.The different Cyclins, specific for the G1-, S-, or M-phases of the cell cycle,[..]

Despite tremendous diversities in their expression, cellular activities in virtually all cell types are regulated by common intracellular signaling systems, and calcium is one important ubiquitous intracellular messenger, controlling a diverse range of cellular processes, such as gene transcription, muscle contraction and cell proliferation. In response to adequate stimuli, [Ca2+]i (Intracellular Ca2+ concentration) increases, oscillates and decreases, leading to the activation, modulation and termination of cell function. Numerous channels and pumps allow this particular cation to enter and exit cells and move between the cytosol and intracellular stores(Ref.1).    When calcium signaling is stimulated in a cell, Ca2+ enters the cytoplasm from one[..]

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 (Cyclic Adenosine 3',5'-monophosphate) 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 and physical properties of the R subunit isoforms,[..]

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[..]

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[..]