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Pathway Central

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Cytokine and Inflammatory Response related Pathways

Activation of cAMP-Dependent PKA [ Details | Top ]
cAMP (Cyclic Adenosine 3',5'-monophosphate) is the first identified second messenger, which has a fundamental role in the cellular response to many extracellular stimuli. The cAMP signaling pathway controls a diverse range of cellular processes. Indeed, not only did cAMP provide the paradigm for the second messenger concept, but also provided the paradigm for signaling compartmentalization. The different receptors, chiefly the GPCRs (G-Protein Coupled Receptors), Alpha and Beta-ADRs (Adrenergic Receptors), Growth Factor receptors, CRHR (Corticotropin Releasing Hormone Receptor), GcgR (Glucagon Receptor) ...

Akt Signaling [ Details | Top ]
Akt (v-Akt Murine Thymoma Viral Oncogene)/ PKB (Protein Kinase-B) is a Serine/threonine Kinase that is involved in mediating various biological responses, such as inhibition of Apoptosis and stimulation of cell proliferation. Three mammalian isoforms are currently known: Akt1/PKB- Alpha, Akt2/PKB-Beta and Akt3/PKB-Gamma. 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 products such as PIP2 (Phosphatidylinositol-3,4-Bisphosphate) and PIP3 (Phosphatidylinositol-3,4,5-Triphosphate)....

B-cell Receptor Pathway - New [ Details | Top ]
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. They are integral membrane proteins. They are present in thousands of identical copies exp...

cAMP Pathway [ Details | Top ]
cAMP (Cyclic Adenosine 3',5'-monophosphate) is the first identified second messenger, which has a fundamental role in the cellular response to many extracellular stimuli. The cAMP signaling pathway controls a diverse range of cellular processes. Indeed, not only did cAMP provide the paradigm for the second messenger concept, but also provided the paradigm for signaling compartmentalization. The different receptors, chiefly the GPCRs (G-Protein Coupled Receptors), Alpha and Beta-ADRs (Adrenergic Receptors), Growth Factor receptors, CRHR (Corticotropin Releasing Hormone Receptor), GcgR (Glucagon Receptor), DCC...

Caspase Cascade [ Details | Top ]
Caspases are a family of cysteine proteases that act in concert in a cascade triggered by apoptosis signaling. The culmination of this cascade is the cleavage of a number of proteins in the cell, followed by cell disassembly, cell death, and, ultimately, the phagocytosis and removal of the cell debris. The Caspase cascade is activated by two distinct routes: one from cell surface and the other from mitochondria (Ref.1). The pathway leading to Caspase activation varies according to the apoptotic stimulus. Initiator Caspases (including 8, 9, 10 and 12) are closely coupled to pro-apototic signals. Pro-apoptotic stimuli include the FasL (Fas Ligand), TNF...

CD40 Signaling - New [ Details | Top ]
CD40, a TNFR (Tumor Necrosis Factor Receptor) family member, conveys signals regulating diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death. First identified and functionally characterized on B-Cells, CD40 is expressed on a plethora of different cell types, including B-Cells, macrophages, dendritic cells, endothelial cells, and fibroblasts, and this widespread expression accounts for the central role of CD40 in the regulation of immune response and host defense (Ref.1). Binding of CD40 with its counter receptor, CD154 (also termed CD40L [CD40 ligand] or GP39), act...

Chemokine Signaling [ Details | Top ]
Chemokines, or chemotactic cytokines, are a large family of small (6-14 kDa), structurally related proteins that mediate a wide range of biological activities. As a part of normal immune system functions, chemokines are a critical component of basal leukocyte trafficking essential for immune system architecture and development, and immune surveillance. Chemokines also participate in the growth, differentiation, and activation of leukocytes as well as stimulate various effector functions of these cells, such as integrin activation, chemotaxis, superoxide radical production and granule enzyme release. Four classes of chemokines...

CREB Pathway [ Details | Top ]
The process of consolidating a new memory and the dynamic complexity of information processing within neuronal networks is greatly increased by activity-dependent changes in gene expression within individual neurons. A leading paradigm of such regulation is the activation of the nuclear transcription factor CREB (cAMP Responsive Element Binding Protein), and its family members the ATF (Activating Transcription Factor) and CREM (cAMP Response Element Modulator), which belong to bZIP (basic/leucine zipper) class of transcription factors that functions in vivo to regulate the proliferation of pituitary cells and thymocytes...

Cytokine Network [ Details | Top ]
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. Furthermore, they are involved in processes of inflammation and in the neuronal, haematopoietic and embryonal development of an organism....

ERK Signaling [ Details | Top ]
The MAPK (Mitogen-Activated Protein Kinase) pathway is one of the primordial signaling systems that nature has used in several permutations to accomplish an amazing variety of tasks. It exists in all eukaryotes, and controls such fundamental cellular processes as Proliferation, Differentiation, Survival and Apoptosis. Mammalian MAPK can be divided into four groups based on their structure and function: ERKs (Extracellular signal-Regulated Kinases), p38MAPKs, JNKs (c-Jun NH2-terminal Kinases) and ERK5 (Extracellular signal-Regulated Kinase-5) or BMK. Activation of these MAPKs occurs through a cascade of upstream kinases...

FGF Pathway [ Details | Top ]
Angiogenesis, the growth of new blood vessels, plays a key role in many physiological and pathological processes, such as ovulation, embryogenesis, wound repair, inflammation, malignant tumor growth, retinopathies, rheumatoid arthritis, and angiogenesis-dependent diseases. One of the best-characterized modulators of angiogenesis is the heparin-binding FGF (Fibroblast Growth Factor). FGF induces neovascularization in vivo and is implicated in the growth of new blood vessels during wound healing and embryogenesis. In vitro, FGF induces cell proliferation, migration, and production of proteases in endothelial cells by interacting...

Glucocorticoid Receptor Signaling [ Details | Top ]
Our bones get more brittle with increasing age, and to add insult to injury, the most effective therapy for another problem that is associated with getting older, rheumatoid arthritis, often adds to the problem by causing bone resorption. The Glucocorticoid steroids, are the best available anti-inflammatories, and are used widely in the treatment of arthritis, as well as other inflammatory conditions such as dermatitis and autoimmune diseases. The Glucocorticoids, secreted by the Adrenal Cortex are powerful anti-inflammatory compounds due to their ability to inhibit all stages of the inflammatory ...

GPCR Pathway [ Details | Top ]
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...

IL-10 - New [ Details | Top ]
IL-10 (Interleukin-10) is a pleiotropic cytokine with important immunoregulatory functions whose actions influence activities of many of the cell-types in the immune system. It is a cytokine with potent anti-inflammatory properties, repressing the expression of inflammatory cytokines such as TNF-Alpha (Tumor Necrosis Factor-Alpha), IL-6 (Interleukin-6) and IL-1 (Interleukin-1) by activated macrophages. Functional IL-10R (IL-10 Receptor) complexes are tetramers consisting of two ligand-binding subunits (IL-10R-Alpha or IL-10R1) and two accessory signaling subunits (IL-10R-Beta or IL-10R2). Binding of IL-10 to the extracellu...

IL-2 Pathway - New [ Details | Top ]
IL-2 (Interleukin-2) is a T-Cell-derived cytokine important in the regulation of growth and differentiation of T-Cells, B-Cells, natural killer cells, glioma cells, and cells of the monocyte lineage after specifically interacting with its receptors. Human IL-2 is a 133-amino acid polypeptide with a molecular mass of 15-18 kDa. IL-2 signaling is mediated by a multichain receptor complex consisting of an alpha (CD25), beta (CD122), and gamma (CD132) chain. The IL-2R (IL-2 Receptor) alpha subunit primarily increases the affinity of ligand binding and is not known to contain a signaling domain, whereas the beta and gamma subun...

IL-6 Pathway - New [ Details | Top ]
IL-6 (Interleukin-6) is a cytokine that provokes a broad range of cellular and physiological responses, including the immune response, inflammation, hematopoiesis, and oncogenesis by regulating cell growth, gene activation, proliferation, survival, and differentiation. IL-6 signals through a receptor composed of two different subunits, an alpha subunit that produces ligand specificity and GP (Glycoprotein) 130, a receptor subunit shared in common with other cytokines in the IL-6 family. Binding of IL-6 to its receptor initiates cellular events including activation of JAK (Janus Kinase) kinases and activation of Ras-mediate...

iNOS Signaling - New [ Details | Top ]
Microorganisms have developed several mechanisms to survive in their hosts' environments. These include competition with their hosts for metal acquisition and resistance to host defenses such as NO (Nitric Oxide), a cytotoxic weapon generated by macrophages. In eukaryotic cells, NO is metabolically produced by NOS (NO Synthase) from L-Arginine, O2 (Molecular Oxygen), and NADPH (Nicotinamide Adenine Dinucleotide, Reduced). In macrophages, an inducible NO synthase (iNOS or NOS2) is produced after activation by endotoxins or cytokines and generates copious amounts of NO presumably to help kill or inhibit the growth of invadin...

Insulin Receptor Pathway [ Details | Top ]
Insulin is the major hormone controlling critical energy functions such as glucose and lipid metabolism. Insulin elicits a diverse array of biological responses by binding to its specific receptor (Ref.1). The insulin receptor belongs to a subfamily of receptor tyrosine kinases that includes the IGF (Insulin-like Growth Factor) receptor and the IRR (Insulin Receptor-Related Receptor). These receptors are tetrameric proteins consisting of two alpha and two beta subunits that function as allosteric enzymes in which the alpha subunit inhibits the tyrosine kinase activity of the beta subunit. Insulin has diverse effects on cells ...

LDL Oxidation in Atherogenesis - New [ Details | Top ]
Atherosclerosis, a chronic inflammatory disease of the arterial wall, is the major cause of morbidity and mortality from CVD (Cardiovascular Disease) in much of the worlds population. The disease involves the formation of Plaques in arterial walls that narrow the arterial passage, restricting blood flow and increasing the risk of occlusion of blood flow by a myocardial infarction. There is now a consensus that Atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The Oxidative Modification hypothesis predicts LDL (Low-Density Lipoproteins) oxid...

MAPK family pathway [ Details | Top ]
Protein kinases are ubiquitous enzymes that are able to modulate the activities of other proteins by adding phosphate groups to their tyrosine, serine, or threonine amino acids (phosphorylation). MAPKs (Mitogen-Activated Protein Kinases), which are activated by many different signals, belong to a large family of serine/threonine protein kinases that are conserved in organisms as diverse as yeast and humans. MAPKs deliver extracellular signals from activated receptors to various cellular compartments, notably the nucleus, where they direct the execution of appropriate genetic programs, including activation of gene transcription...

MAPK Signaling [ Details | Top ]
Intracellular signaling cascades are the main routes of communication between the Plasma membrane and regulatory targets in various intracellular compartments. Sequential activation of Kinases is a common mechanism of signal transduction in many cellular processes. During the past decade, several related intracellular signaling cascades have been elucidated, which are collectively known as MAPK (Mitogen-Activated Protein Kinase) signaling cascades. The MAPKs are a group of protein Serine/threonine Kinases that are activated in response to a variety of extracellular stimuli and mediate ....

NF-KappaB Family Pathway [ Details | Top ]
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...

NFAT and cardiac hypertrophy [ Details | Top ]
Cardiac failure, one of the largest health care burdens in the United States and other developed countries is often associated with prolonged and maladaptive cardiac hypertrophy, defined as a compensatory mechanism of the heart that helps to maintain cardiac output during pathological states with sustained increases in hemodynamic load (Ref.1). As cardiomyocytes lose the ability to divide soon after birth, cardiac hypertrophy offers an important adaptive response in vivo that allows the organism to maintain or increase its cardiac output. The adult myocardium responds to a wide array of intrinsic...

NGF Pathway [ Details | Top ]
One of the most fundamental issues in current biology is how to maintain the critical balance between cell survival and death, both during development and in adulthood. Unrestrained cell division and survival leads to various forms of tumor, while excessive or premature cell death may lead to a variety of diseases such as Alzheimer's, Parkinson's and Multiple Sclerosis. In the nervous system, a family of Neurotrophins, which includes NGF (Nerve Growth Factor), BDNF (Brain Derived Neurotrophic Factor), NT3 (Neurotrophin3) and NT4/5 (Neurotrophin-4/5), maintains this critical balance of cell survival and death. The best characterized of these...

PI3K Signaling in B-Lymphocyte - New [ Details | Top ]
PI3Ks (Phosphoinositide-3-Kinases) regulate numerous biological processes, including cell growth, differentiation, survival, proliferation, migration and metabolism. In the immune system, impaired PI3K signaling leads to immunodeficiency, whereas unrestrained PI3K signaling contributes to autoimmunity and Leukemia. The Class I and III PI3Ks basically facilitate B-cell development through defined stages, resulting in at least three distinct lineages of mature B-lymphocytes. In B-cells, PI3K is activated within seconds of antigen-receptor triggering. The BCR (B-Cell antigen Receptor) plays a critical role in recognition of a...

Ras Pathway [ Details | Top ]
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...

SMAD Signaling Network [ Details | Top ]
Within the vasculature, TGF-Beta (Transforming Growth Factor-Beta) superfamily of secreted polypeptide growth factors play an important role in a variety of pathophysiologic processes, including angiogenesis, vascular remodeling, atherogenesis and in regulating cellular responses such as growth, proliferation, differentiation, migration, adhesion, survival, and specification of developmental fate. Apart from TGF-Beta, the superfamily also includes the Activins and the BMPs (Bone Morphogenetic Proteins). These factors signal through heteromeric complexes of Type-II and Type-I serine-threonine...

STAT3 Pathway - New [ Details | Top ]
STATs (Signal Transducers and Activators of Transcription) are a family of cytoplasmic proteins with SH2 (Src Homology-2) domains that act as signal messengers and transcription factors and participate in normal cellular responses to Cytokines and GFs (Growth Factors). STATs are activated via the tyrosine phosphorylation cascade after ligand binding and stimulation of the Cytokine Receptor-Kinase complex and Growth Factor-Receptor complex like the EGF (Epidermal Growth Factor), FGF (Fibroblast Growth Factor), PDGF (Platelet-Derived Growth Factor), GCSF (Granulocyte Colony Stimulating Factor), IL-6 (Interleukin-6), CNTF (Ci...

TCR Signaling - New [ Details | Top ]
T-Cells are a subset of lymphocytes that play a large role in the immune response. The TCR (T-Cell Receptor) is a complex of integral membrane proteins that participates in the activation of T-Cells in response to the presentation of antigen. Stimulation of TCR is triggered by MHC (Major Histocompatibility Complex) molecules on Antigen Presenting Cells that present antigen peptides to TCR complexes and induce a series of intracellular signaling cascades. Engagement of the TCR initiates positive (signal-enhancing) and negative (signal-attenuating) cascades that ultimately result in cellular proliferation, differentiation, c...

TGF-Beta Pathway [ Details | Top ]
Cell proliferation in somatic tissues, specification of cell fate during embryogenesis, differentiation and cell death are controlled by a multitude of cell–cell signals and loss of this control has devastating consequences. Prominent among these regulatory signals is the TGF-Beta (Transforming Growth Factor) super family, which comprises a large and diverse group of polypeptide morphogens including the prototype of the family–the TGF-Beta themselves as well as the BMPs (Bone Morphogenetic Proteins), and the GDFs (Growth and Differentiation Factors) (Ref.1). The members of the TGF-Beta family are expressed in distinct temporal...

TNF Signaling [ Details | Top ]
TNF (Tumor Necrosis Factor) is a multifunctional proinflammatory cytokine, with effects on lipid metabolism, coagulation, insulin resistance, and endothelial function. TNF has been considered as an anti-cancer agent since its discovery two decades ago. Members of the TNFR (TNF Receptor) superfamily can send both survival and death signals to cells (Ref.1). TNF family members play important roles in various physiological and pathological processes, including cell proliferation, differentiation, apoptosis, modulation of immune responses and induction of inflammation. TNF acts through two receptors, TNFR1 (TNF Receptor-1) and TNFR2 (TNF Receptor-2)....

TNF Superfamily Pathway [ Details | Top ]
Members of the TNF (Tumor necrosis factor) receptor superfamily play pivotal roles in numerous biological events in metazoan organisms. Ligand-mediated trimerization by corresponding homo- or hetero-trimeric ligands, the TNF family proteins, causes recruitment of several intracellular adaptors, which activate multiple signal transduction pathways. 29 TNF receptor family members have been identified in humans. Based upon their cytoplasmic sequences and signaling properties, these TNF receptors can be classified into three major groups (Ref.1). The first group, including Fas/ CD95/ Apo1/ APT1, TNFR1/ CD120a...

Toll-Like Receptors Pathway [ Details | Top ]
TLRs (Toll-like receptors) are transmembrane proteins expressed by cells of the innate immune system, which recognize invading microbes and activate signaling pathways that launch immune and inflammatory responses to destroy the invaders. Toll receptors were first identified in Drosophila. In mammals, the TLR family includes eleven proteins (TLR1−TLR11). Recently, two new members, TLR12 and TLR13 have been discovered in mouse, but not much information is known about them. Mammalian TLRs consist of an extracellular portion containing Leucine-rich repeats, a Transmembrane region and a Cytoplasmic tail...

Transendothelial Migration of Leukocytes - New [ Details | Top ]
The migratory properties of leukocytes or WBCs (White Blood Cells) are indispensable to drive immune responses throughout the body. Leukocytes fall under two categories according to their morphology that includes Agranulocytes (Lymphocytes and Monocytes) and Granulocytes (Neutrophils, Basophils and Eosinophils). To ensure migration to the proper locations, the trafficking of leukocytes is tightly regulated. The vascular endothelium lining the intima of the blood vessels (both in lymphoid and non-lymphoid tissues) regulates a variety of functions including vascular smooth muscle tone, host-defense reactions, Angiogenesis, a...

VEGF Pathway [ Details | Top ]
The formation of blood vessels occurs either by in situ differentiation of endothelial cell precursors (Angioblasts) and association of these cells to form primitive vessels, a process called Vasculogenesis, or by growth of preexisting vessels, a process called Angiogenesis. Vasculogenesis establishes the primary vascular plexus of the early embryo, whereas development of blood vessels during later embryogenesis and adult life occurs primarily by Angiogenesis. Angiogenesis is an integral feature of capillary sprouts from preexisting blood vessels. It is typically quiescent in the adult, except for pathological situations...

WNT Signaling [ Details | Top ]
The development of tissues and organs in multicellular organisms is controlled by the interplay of several signaling pathways that cross talk to provide positional information and induce cell fate specification. Together with other families of secreted factors such as TGF-Betas (Transforming Growth Factor-Betas), FGFs (Fibroblast Growth Factors), Hedgehog and Notch proteins, WNT (Wingless-Type MMTV Integration Site Family) Growth Factors are crucially implicated in these processes. The WNT genes encode a large family of secreted protein growth factors that have been identified in animals from Hydra to Human...