Lymphocytes are one of the five kinds of white blood cells or leukocytes, circulating in the blood. Although mature lymphocytes all look pretty much alike, they are extraordinarily diverse in their functions. The most abundant lymphocytes are: B-Lymphocytes (often simply called B-Cells) and T-Lymphocytes (likewise called T-Cells) [Ref.1]. B-Cells are not only produced in the bone marrow but also mature there. Each B-Cell is specific for a particular antigen. The specificity of binding resides in the BCR (B-Cell receptor) for antigen [Ref.2]. Mature B cells express two BCR isotypes, IgM and IgD. The BCR is composed of mIg (membrane immunoglobulin); a structure of four (in the case of IgD) or five (IgM) immunoglobulin domains in the heavy chain linked by a hinge, and a[..]

The SM (Sphingomyelin) pathway is an evolutionarily conserved stress response system linking diverse environmental stresses (Ultraviolet, Heat Shock, Oxidative Stress, and Ionizing Radiation) to cellular effector pathways. Ceramide is the second messenger in this system and can be generated either by hydrolysis of SM through SM-specific PLC (Phospholipase-C) termed SMases (Sphingomyelinases) or by de novo synthesis through the enzyme Ceramide Synthase . There are two classes of SMase, acidic (A-Smase) and neutral (N-Smase). Stress stimuli such as, TNF-Alpha (Tumor Necrosis Factor-Alpha), lipopolysaccharide, and some chemotherapy drugs such as doxorubicin also mediate apoptosis by generation of the lipid second messenger, Ceramide. A specific interaction between the FAN[..]

The ability of multicellular organisms to maintain cellular homeostasis is critically dependent on a balance between cell survival and cell death (apoptosis). The responsiveness of individual cells to death signals varies greatly depending on the presence of continuous survival cues from the extracellular environment. The perturbation of normal cell survival mechanisms, leading to an increase in cell survival or cell death plays an important role in the development of a number of disease states, including cancer. BAD (BCL2 Associated Death Promoter) is a pro-apoptotic critical regulatory component of the intrinsic cell death machinery that exerts its death-promoting effect upon heterodimerization with the antiapoptotic proteins of the BCL2 family defined by conserved[..]

TGFB (Transforming growth factor-beta) is a multifunctional cytokine that regulates a wide variety of cellular functions, including cell growth, cellular differentiation, apoptosis, and wound healing. TGF-b signals are transmitted through two transmembrane serine/threonine kinase receptors TGFBR1 and TGFBR2 [Ref.1]. Initiation of the TGFB signaling cascade occurs upon ligand binding to TGFB receptor TGFBR2 and subsequent TGFBR1– TGFBR2 heterotetrameric complex formation. TGFBR2 is a constitutively active receptor kinase and phosphorylates Ser/Thr residues in the cytoplasmic GS domain of TGFBR1, which turns on the kinase activity of TGFBR1. Upon Activation, TGFBR1 transmits its signal to the various intracellular SMAD-dependent and SMAD independent signaling[..]

Dynamic regulation of the actin cytoskeleton underpins a multitude of cellular processes, from cell movement and polarization1,2 to cell division.3 The actin cytoskeleton and the proteins involved in its regulation are also fundamentally linked to endocytosis and membrane trafficking.4,5 Members of the Rho family of small GTPases have emerged as important overseers of the actin cytoskeleton and a number of Rho family members and their downstream effector proteins have been linked to specific actin pathways. Among the Rho family actin regulators is Cdc42 is a small GTPase responsible for a large number of eukaryotic cell signaling pathways(Ref.1).CDC42 acts downstream of cell surface receptors to regulate the formation of different F-actin-containing structures. It[..]

Ran is a member of the Ras family of small GTPases. The Ran subgroup is represented by its lone member, Ran, that is distinguished from Ras GTPases by its lipid modification and atypical subcellular localization. Unlike most other Ras-related proteins, Ran is not modified to bind to cell membranes. Instead, Ran protein is localized throughout the cell, where it is concentrated primarily in the nucleus (Ref.1). Ran is regulated by a cytosolic RanGAP1 (Ran GTPase–Activating Protein-1) and by a RanGEF (Chromatin-Bound Guanine Nucleotide Exchange Factor). The distribution of RanGTP provides important spatial information that directs cellular activities during different parts of the cell cycle. During interphase, the localization of RanGEF and RanGAP1 predicts that[..]

Our immune system is largely controlled by the action of pleiotropic cytokines and growth factors, small secreted proteins, which bind to receptors on the surface of immune cells to initiate an appropriate physiological response. The cellular response to cytokines and growth factors is predominantly executed by intracellular proteins known as the Janus kinases (JAKs) and the signal transducers and activators of transcriptions (STATs). These  kinases activated upon ligand binding causes the phosphorylation of tyrosine residues within the receptor intracellular region and phosphorylation of other signalling proteins recruited to the receptor complex like signal transducers and activators of transcriptions (STATs). Once phosphorylated, STATs translocate to the[..]

Calpain is an evolutionary old family of soluble, neutral, calcium-dependent proteases, which have the unique property of using protein cleavage to modify the activity/function of their substrate proteins. There are two major calpain isoforms in the brain, calpain-1 and calpain-2. Calpain-1 and Calpain-2 exhibit opposite functions in both synaptic plasticity and neurodegeneration. Calpain-1 activation is required for the induction of long-term potentiation (LTP) and is generally neuroprotective, while calpain-2 activation limits the extent of potentiation and is neurodegenerative. Calpains release the link between the integrin-dependent FA complex and the actin cytoskeleton by proteolysis of talin, which allows proper cell migration. The activity of Calpains is tightly[..]

Members of the TNFR (Tumor Necrosis Factor Receptor) superfamily are important for cell growth and survival. CD27 is a member of the TNFR superfamily, which includes TNFR types I and II, NGFR (Nerve Growth Factor Receptor), CD30 (associated with Hodgkin lymphoma), Fas/Apo1 (CD95), CD40, 4–1BB, and OX40. These receptors are known to play a very important role in cell growth and differentiation, as well as apoptosis or programmed cell death. In addition to providing costimulatory signals for cell proliferation, ligation of both TNFR1 and Fas can result in programmed cell death or apoptosis. The underlying mechanism requires an intact 80-aa stretch present in the cytoplasmic tails of both TNFR1 and Fas, termed the DD (Death Domain) (Ref.1). CD27 is a disulfide-linked[..]

PKR (Protein Kinase-R) is a 68-kDa serine–threonine kinase that appears to play a primary role in mediating the antiviral activities of infected cells. PKR mediates apoptosis induced by many different stimuli, such as LPS (Lipopolysaccharides), TNF-Alpha (Tumour Necrosis Factor-Alpha), viral infection, or serum starvation. Viral infection leads to the increased expression and secretion of the cytokine IFN-Gamma (Interferon- Gamma) from host cells. IFN-gamma induces the dsRNA (Double-Stranded RNA)-dependent PKR. dsRNA, produced during viral replication, is an active component of a viral infection that stimulates antiviral responses in infected cells (Ref.1). The PKR protein is enzymatically inactive unless it is activated by binding to dsRNA. PKR activates as a kinase[..]

The Eph family forms the largest group of RTKs (Receptor Tyrosine Kinases) comprising 14 members in mammals that play critical roles in diverse biological processes during development as well as in the mature animal. They are activated by membrane-bound ligands called Ephrins, which are classified into two subclasses based on their mode of membrane anchorage. The Ephrin-A ligands are GPI (Glycosylphosphatidylinositol)-linked and prefer to bind to EphA Receptors. The Ephrin-B ligands (Ephrin-B1–B3), which possess a transmembrane moiety and a short cytoplasmic domain, bind to EphB Receptors (EphB1–B6). The interactions between Ephrins and Eph Receptors are generally promiscuous within each subclass (Ref.1). Upon stimulation by Ephrin ligands, Eph Receptors[..]

Ras is a membrane-associated guanine nucleotide-binding protein that is normally activated in response to the binding of extracellular signals, such as growth factors, RTKs (Receptor Tyrosine Kinases), TCR (T-Cell Receptors) and PMA (Phorbol-12 Myristate-13 Acetate). Ras signaling affects many cellular functions, which includes cell proliferation, apoptosis, migration, fate specification, and differentiation. Ras acts as a binary signal switch cycling between ON and OFF states, which are characterized in terms of a small molecule, a guanine nucleotide, bound to the protein. In the resting cell, Ras is tightly bound to GDP (Guanosine Diphosphate), which is exchanged for GTP (Guanosine Triphosphate) upon binding of extracellular stimuli to cell membrane receptors. In the[..]