APRIL (a proliferation-inducing ligand, also known as TRDL-1, TALL-2, and TNFSF13), is a member of the TNF (tumor necrosis factor) superfamily, with homologous structure and function to several other cytokines in this family. It is a cytokine which is over-expressed by transformed cells and could stimulate cellular proliferation (Ref.1) It has two receptors i.e BCMA and TACI (Tumor necrosis factor receptor superfamily members 17 and 13B) that play important roles in the B-cell and T-cell arms of the immune system (Ref.2 & 3). One of the most important APRIL-induced mechanism is an activation of NF-kB (Nuclear factors of kappa light polypeptide in B-cells) signaling cascades. Activation and nuclear translocation of NF-kB proteins can occur by one of two pathways:[..]

BAFF (B-cell activating factor), is a member of the TNF (tumor necrosis factor) ligand family that plays important roles in B-cell homeostasis, tolerance, and malignancy (Ref.1). It is also known as BLyS (B lymphocyte stimulator) protein, TALL-1 (TNF and apoptosis ligand-related leukocyte-expressed ligand-1), zTNF4, CD257, TNFSF13B, TNFS20 (TNF superfamily member) and THANK (TNF homolog that activates apoptosis, NF-B and c-Jun NH2-terminal kinase). It functions through three receptors i.e. TACI, BCMA and BAFFR (BAFF-receptor) (Ref.1). Interaction of BAFF with BAFFR leads to recruitment of TRAF3 to the receptor and it is subsequently degraded by the combined actions of TRAF2 and cIAP1/2 (Ref.2). Lack of TRAF3 deactivates the TRAF/cIAP complex, releasing NIK and[..]

Protein synthesis in eukaryotic organisms is a complex process that requires cooperation among a large number of polypeptides including ribosomal proteins, modification of enzymes, and ribosome-associated translation factors. The initiation phase of protein synthesis, during which ribosomes select mRNAs to be translated and identify the translational start site, requires a set of eIFs (eukaryotic Translation Initiation Factors), many of which are comprised of multiple polypeptide subunits. EIF2 (Eukaryotic Initiation Factor-2) is a GTP (Guanosine Triphosphate)-binding protein that escorts the initiation-specific form of Met-tRNA (Met-tRNAi) onto the ribosome. It is composed of 3 non-identical subunits, alpha (36 kD), beta (38 kD), and gamma (52 kD). cDNAs for each of[..]

The ERBB (Erythroblastic Leukemia Viral Oncogene Homolog) family of transmembrane RTKs (Receptor Tyrosine Kinases) plays an important role in the pathogenesis of many cancers. This family is comprised of four members EGFR (Epidermal Growth Factor Receptor), ERBB2, ERBB3, and ERBB4, ERBB2 also called HER2 (Heregulin-2) and ERBB3 are closely related to the EGFR/ERBB1, but unlike EGFR, ERBB2 is a ligandless receptor, whereas ERBB3 lacks tyrosine kinase activity. Hence, both ERBB2 and ERBB3 are active only in the context of ERBB heterodimers, and ERBB2-ERBB3 heterodimers, which are driven by NRG (Neuregulin) ligands, are the most prevalent and potent complexes in terms of cell growth and transformation. The basis for the potency of signaling by the ligand-activated[..]

Protein synthesis regulation in eukaryotes is important for the modulation of gene expression. The process of mRNA translation/protein synthesis is generally initiated by eukaryotic initiation factors (eIFs), which along with p70S6K play critical roles in translational regulation (Ref.1). During mRNA translation, eukaryotic initiation factor 4E (eIF4E) (the m7GTP cap-binding protein) binds to eIF4G (a scaffolding subunit) and eIF4A (an ATP-dependent RNA helicase) to form active eIF4F complex.  eIF4F complex binds to the 7-methyl-GTP cap structure present at the 5’ termini of all eukaryotic mRNAs and recruit the ribosome near the 5’ terminus of mRNA. PABP (Poly (A)-Binding Protein) also play an important role in the recruitment of mRNAs to ribosomes[..]

The ERBB (Erythroblastic Leukemia Viral Oncogene Homolog) or EGF (Epidermal Growth Factor) family of transmembrane RTKs (Receptor Tyrosine Kinases) plays an important role during the growth and development of a number of organs including the heart, the mammary gland, and the central nervous system. In addition, ERBB overexpression is associated with tumorigenesis of the breast, ovaries, brain, and prostate gland. The ERBB family includes four members, EGFR (EGF Receptor)/ERBB1/HER1 (Heregulin-1), ERBB2/HER2 (Heregulin-2), ERBB3/HER3 (Heregulin-3), and ERBB4/HER4 (Heregulin-4).Two of the family members, ERBB1 and ERBB2, are involved in the development of many types of human cancer. All ERBBs have in common an extracellular ligand-binding domain, a single[..]

ERBB4 (Erythroblastic Leukemia Viral Oncogene Homolog-4) is a 180-kDa transmembrane RTK (Receptor Tyrosine Kinase) that regulates cell proliferation and differentiation. The ERBB4 is a member of the EGFR (epidermal growth factor receptor) subfamily of transmembrane RTKs. ERBB4 is expressed in several tissues, mainly heart, mammary gland and the central nervous system. ERBB4 and its ligands have important roles in normal cardiovascular and neural development, differentiation of the mammary gland, and in pathological conditions, such as heart diseases and cancer (Ref.1).ERBB4 can be activated by at least seven members of EGF-related peptide growth factors: betacellulin, epiregulin, HB-EGF (heparin-binding EGF-like growth factor) and the neuregulins (NRG-1, NRG-2, NRG-3,[..]

Killer lymphocytes are key players in the effector arm of the immune response that eliminate cells infected with intracellular pathogens and transformed tumor cells. Killer cells in both adaptive and innate immunity-T cells (CTLS) and natural killer (NK) cells, respectively, use the same basic mechanisms for destroying their targets, although they are triggered by distinct receptors and the expression of cytotoxic granules is constitutive in NK cells, but regulated in T cells. Release of the contents of cytotoxic granules into the immunological synapse formed between the killer cell and its target cell is important for immune elimination of viruses, intracellular bacteria, and tumors. Granzyme-A (GzmA), a tryptase and B (GzmB), serine protease, are the most abundant[..]

NF-KappaB (Nuclear Factor-KappaB) is a heterodimeric protein composed of different combinations of members of the Rel family of transcription factors. The Rel/ NF-KappaB family of transcription factors are involved mainly in stress-induced, immune, and inflammatory responses. In addition, these molecules play important roles during the development of certain hemopoietic cells, keratinocytes, and lymphoid organ structures. More recently, NF-KappaB family members have been implicated in neoplastic progression and the formation of neuronal synapses. NF-KappaB is also an important regulator in cell fate decisions, such as programmed cell death and proliferation control, and is critical in tumorigenesis (Ref.1).NF-KappaB is composed of homo- and heterodimers of five members[..]

PKR (Protein kinase-R) is a ubiquitously expressed serine-threonine kinase that has been implicated as a signal integrator in translational and transcriptional control pathways.  PKR mediate apoptosis induced by many different stimuli, such as LPS (Lipopolysaccharides), IFN-Gamma (Interferon-Gamma), cytokines, growth factor, viral infection, or serum starvation.  PKR activity is regulated by external signals, which act on proteins, which interact with PKR. Among the proteins identified so far are p58, a cellular protein, K3L, the product of a gene of vaccinia virus,  PACT  (Protein Activator Of Interferon-Induced Protein Kinase) and p67, an interferon-induced glycoprotein (Ref.1). Human PKR is a 68 kDa with a 20 kDa N-terminal dsRBD[..]

Complement is a complex system containing more than 30 various glycoproteins present in serum in the form of components, factors, or other regulators and/or on the surface of different cells in the form of receptors. It is a highly sophisticated host defence system designed to destroy pathogens. Once the complement system is activated, a chain of reactions involving proteolysis and assembly occurs, resulting in destruction of the membranes of pathogens. The cascade up to the cleavage of C3 (Complement component 3), which plays a central role in the complement system, is called the activation pathway. There are three categories of complement pathway; the classical pathway, alternative pathway and lectin pathway (Ref.1).The recently discovered lectin pathway (also called[..]

Antigenic stimulation of lymphocytes and other cells of the immune system initiates a complex series of intracellular signal transduction pathways that lead to the expression of a panel of immunoregulatory genes, whose function is critical to the initiation and coordination of the immune response. NFATs (Nuclear Factors of Activated T-Cells), a family of transcription factors expressed both inside and outside of diverse cell types of the immune system, play a pivotal role in the process. Originally described in T-Cells, NFATs have now been implicated in the activation of mast cells, B-Cells, NK (Natural Killer) cells, monocytes, and play a key role in the expression of a number of immunologically important genes, including a wide array of cytokines: IL-2, IL-3,[..]