AHR is a cytosolic receptor for low molecular weight molecules, binding and becoming activated by sterically planar ligands approximately three benzene rings in size. It is maximally expressed in interface tissues including the liver, lungs, skin and gastrointestinal tract [Ref.1]. It is recognized as the culprit for most toxic responses observed after exposure to PAH (Polycyclic Aromatic Hydrocarbons), Dioxins (e.g. TCDD (2, 3, 7, 8-tetrachlorodibenzo-p-dioxin)), and PCBs(Polychlorinated Biphenyls),3MC,β-NF and B[a]P. It is also activated by FICZ, which is formed upon absorption of UVB by TRP (tryptophan) and results in dissociation of PP60 from the complex [2&3]. AHR can affect cellular signaling through interactions with various Regulatory and Signaling[..]

To thwart viral infection, our cells have developed a formidable and integrated defense network that comprise of innate and adaptive immune responses. In an attempt to prevent viral replication, viral dissemination or persistent viral infection of the cell, many of these protective measures actually involve the induction of programmed cell death, or apoptosis. Once the virus has invaded the cell, a host defense-mediated response is triggered which involves the induction of a family of pleiotropic cytokines known as the IFNs (Interferons) (Ref.1). These IFNs constitute a heterogeneous group of proteins and are best known for their ability to induce cellular resistance to virus infection. However, IFNs also affect many other cellular functions, such as cell growth. IFNs[..]

AKT/PKB Pathway is an evolutionarily conserved serine/threonine kinase Pathway involved in a wide variety of cellular functions, including proliferation, cell survival, differentiation, glucose mobilization, homeostasis, cell migration, and apoptosis. Three isoforms, AKT1,AKT2, and AKT3, are expressed in mammals (Ref.1 & 2). Akt is a central node in cell signaling downstream of growth factors, cytokines, and other cellular stimuli. Aberrant loss or gain of Akt activation underlies the pathophysiological properties of a variety of complex diseases, including type-2 diabetes and cancer (Ref.3). All three isoforms of Akt share a common structure of three domains. The N-terminus of the protein is a PH (Pleckstrin Homology) domain, which interacts with membrane lipid[..]

ATM (Ataxia Telangiectasia Mutated Protein) belongs to a family of Kinases that have sequence homology to PI3K (Phosphoinositide 3-Kinase).ATM is a key regulator of multiple signaling cascades which respond to DNA strand breaks induced by damaging agents IR (Ionizing Radiation), radiometric agents or by normal processes. These responses involve the activation of cell cycle CHK factors (Checkpoints factors), DNA repair and Apoptosis. Its downstream targets include CHK1 (Cell Cycle Checkpoint Kinase-1), CHK2 (Cell Cycle Checkpoint Kinase-2), tumor suppressors like p53 and BRCA (Breast Cancer), DNA repair factors like RAD50, RAD51, GADD45 (Growth Arrest and DNA-Damage-inducible), and other signaling molecules like c-ABL and NF-KappaB (Nuclear Factor-Kappa B) . In[..]

The BCR (B-Cell antigen Receptor) plays a critical role in development, survival, and activation of B cells. The BCR is composed of mIg molecules (Membrane Immunoglobulin) and associated Ig-Alpha/Ig-Beta heterodimer [Ref.1]. The mIg subunits bind antigen and cause receptor aggregation, while the Alpha/Beta subunits transduce signals to the cell interior. Engagement of receptor activates three types of intracellular protein tyrosine kinases, SYK (Spleen Tyrosine Kinase), BTK (Bruton agammaglobulinemia Tyrosine Kinase) and several members of the SRC-family of tyrosine kinases [Ref.2&3]. Once activated, these tyrosine kinases phosphorylate signaling components and thereby activate various signaling pathways, including PIP2 (Phosphatidyl Inositol 4, 5-Bisphosphate)[..]

p14(ARF) is a key component of a major human tumor suppressor pathway that is responsible for arresting cell-cycle progression and inducing cell death in response to DNA damage and oncogenic stress. It plays an important role as an inhibitor of the MDM2-mediated degradation of p53. p14(ARF) activity is linked to its oligomerization and is sensitive to the redox status of the cell. Oxidative stress affects p14(ARF) oligomerization. Tumor promotion is associated with an altered redox status, and it is known that cancer cells produce an excess of ROS (Reactive Oxygen Species). The oligomeric forms of p14(ARF) are sensitive to reducing agents. p14(ARF) binds to MDM2 and promotes its rapid degradation. This interaction is mediated by the Exon1Beta-encoded N-terminal domain[..]

Tumor necrosis factor (TNF) superfamily proteins consisting of 19 members and 29 receptors regulate cell proliferation, cell death, and morphogenesis. The tumor necrosis factor superfamilies members provide key communication signals between various cell types during development, especially in the skin, bones, and lymphoid organs, and maintain organ homeostasis and initiate tissue responses. Because of these essential roles, TNFRSFs and the TNF superfamily (TNFSF) ligands are attractive targets for treating diverse diseases, such as autoimmunity, cancer, infectious diseases, and graft-versus-host disease (Ref.1 and 2). The TNF-related ligands assemble into trimers that form a highly efficient receptor-clustering and signal-initiating mechanism. TNF receptors share a[..]

GPCRs (Guanine Nucleotide Binding–Protein Coupled Receptors) comprise large and diverse gene families in fungi, plants, and the animal kingdom. Also termed serpentine receptors, GPCRs are polytopic membrane proteins that share a common structure with seven transmembrane segments, but sequence similarity is minimal among the most distant GPCRs. Their principal function is to transmit information about the extracellular environment to the interior of the cell, and they do this by interacting with the G-proteins. GPCRs recognize a variety of ligands and stimuli including peptide and non-peptide hormones and neurotransmitters, chemokines, prostanoids and proteinases, biogenic amines, nucleosides, lipids, growth factors, odorant molecules and light. These receptors[..]

Rap1 (Krev-1/smg p21), a small-molecular-weight GTP-binding protein that belongs to the Ras-like superfamily of GTPases, is involved in signal transduction cascades. It is highly homologous to Ras but it is down regulated by its own set of GAPs (GTPase-Activating Proteins). Rap1 is implicated in the regulation of a variety of cellular processes including the control of platelet activation, T-cell anergy, B-Cell activation, and neuronal differentiation. Very recently, Rap was shown to be involved in the control of cell adhesion, in particular the regulation of integrin activation by inside-out signaling. In humans, four isoforms of Rap, Rap1A, Rap1B, Rap2A, and Rap2B, exist. Rap1A  and Rap1B  share more than 90% sequence identity. Rap1A/B is the closest[..]

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[..]