中文名: 分子生物学－－细胞信号通路
英文名: signaling pathway
资源格式: 压缩包
地区: 美国
对白语言: 英语
文字语言: 英文
简介:
Complete List of Pathways
Activation of cAMP-Dependent PKA
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) ...
AHR Pathway
AHR (Aryl Hydrocarbon Receptor) is a member of the bHLH (basic Helix-Loop-Helix)- PAS (Per-ARNT-Sim) family of transcriptional regulators that control a variety of developmental and physiological events, including Neurogenesis, Tracheal and Salivary duct formation, Toxin metabolism, Circadian rhythms, response to Hypoxia and Hormone Receptor function. The unique feature of all bHLH-PAS proteins is the PAS domain, named after the first three proteins identified with this motif, the Drosophila Per, Human ARNT and Drosophila Sim. The PAS domain consists of 260 310 amino acids and incorporates two well-conserved hydrophobic re...
Akt Signaling
Akt (v-Akt Murine Thymoma Viral Oncogene)/ PKB (Protein Kinase-
All-trans-retinoic acid signaling
Retinoic Acid, a lipophilic molecule and a metabolite of Vitamin-A (all-trans-Retinol), affects gene transcription and modulates a wide variety of biological processes like Cell Proliferation, Differentiation, including Apoptosis. Retinoic Acid mediated gene transcription depends on the rate of transport of Retinoic Acid to target cells and the timing of exposure of Retinoic Acid to RARs (Retinoic Acid Receptors) in the target tissues. The all-trans-Retinoic Acid, the Carboxylic Acid form of Vitamin-A is of biological significance since it has high circulating levels than other isomers of Retinoic Acid. The targets of all-trans-Retinoic Acid and RARs include a multitude...
Androgen Signaling
Androgens mediate a wide range of developmental and physiological responses and are especially important in male sexual differentiation and pubertal sexual maturation, the maintenance of spermatogenesis, and male gonadotropin regulation (Ref.1). The principle steroidal androgens, testosterone and its metabolite DHT (5-Alpha-Dihydrotestosterone), mediate their biological effects predominantly through binding to the AR (Androgen Receptor), an androgen-inducible member of the nuclear receptor superfamily of transcription factors (Ref.2)....
Assembly of RNA Polymerase-II Initiation Complex
The nuclei of all eukaryotic cells contain three different RNA Polymerases, designated I, II and III. Like the DNA Polymerase that catalyzes DNA replication, RNA Polymerases catalyze the formation of the phosphodiester bonds that link the nucleotides together to form a linear chain. The RNA Polymerase moves stepwise along the DNA, unwinding the DNA helix just ahead of the active site for polymerization to expose a new region of the template strand for complementary base-pairing. In this way, the growing RNA chain is extended by one nucleotide at a time in the 5’-to-3’ direction. The substrates are nucleoside triphosphates...
ATM Pathway
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. In addition, ATM appears to function as a 'caretaker', suppressing tumorigenesis in specific T cell lineages. Its downstream targets include Chk1 (Cell Cycle Checkpoint Kinase-1), Chk2 (Cell C...
B-cell Receptor Pathway
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...
BRCA1 Pathway
The maintenance of genome integrity is essential to all life, but is particularly important to long-lived multicellular organisms, which are susceptible to cancer. DNA damage can take the form of base modifications, strand breaks, interstrand cross-links and other lesions. To deal with many types of damage, genomes have evolved multiple cellular defense mechanisms, including DNA repair and cell cycle checkpoint processes. Different pathways exist for specific kinds of DNA damage and the cell must have ways to decide which mechanism to use for a given lesion. These requirements imply that signaling networks not only sense t...
cAMP Pathway
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
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
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...
CDK5 Pathway
CDKs (Cyclin-dependent kinases) are a group of serine/threonine protein kinases activated by binding to a regulatory subunit cyclin. These kinases are key regulators of the eukaryotic cell cycle progression. CDK5 (also known as Neuronal CDC2-Like Kinase, NCLK) is a unique member of the CDK family, that does not act as a checkpoint kinase to regulate cell cycle progression, but acts as a regulatory kinase involved in other post-mitotic processes such as neuronal activity, neuronal migration during development and neurite outgrowth. Although the CDK5 protein is expressed at basal levels in most mammalian tissues, CDK5 activi...
Cellular Apoptosis Pathway
Apoptosis is a naturally occurring process by which a cell is directed to Programmed Cell Death. Apoptosis is based on a genetic program that is an indispensable part of the development and function of an organism. In this process, cells that are no longer needed or that will be detrimental to an organism or tissue are disposed of in a neat and orderly manner; this prevents the development of an inflammatory response, which is often associated with Necrotic cell death. There are at least two broad pathways that lead to Apoptosis, an "Extrinsic" and an "Intrinsic" Pathway. In both pathways, signaling results in the activation of a family of Cys (Cysteine)...
Chemokine Signaling
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...
Chromatin Remodeling
The condensation of DNA into an ordered chromatin structure allows the cell to solve the topological problems associated with storing huge molecules of chromosomal DNA within the nucleus. DNA is packaged into chromatin in orderly repeating protein-DNA complexes called nucleosomes. Each nucleosome consists of approximately 146bp of dsDNA (double-stranded DNA) wound 1.8 times around a histone octamer (Ref.1). Two molecules each of H2A, H2B, H3, and H4 comprise the histone ramp around which the DNA superhelix winds. Stretches of DNA upto 100bp separate adjacent nucleosomes...
Circadian Clock in Mammals
Circadian clocks are molecular time-keeping mechanisms that reside in a diverse range of cell types in a variety of organisms. The primary role of these cell-autonomous clocks is to maintain their own 24-hour molecular rhythm and to drive the rhythmic expression of genes involved in physiology, metabolism and behavior. The ability of the clock to persist in the absence of environmental cues provides internal temporal organization so that rhythmic activities can occur at characteristic times during the circadian cycle. In addition, two other clock properties, entrainment (that is, setting the clock to local time with respec...
CREB Pathway
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...
Cyclins and Cell Cycle Regulation
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...
Cytokine Network
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....
DNA Methylation and Transcriptional Repression
Transcriptional repression is an essential mechanism in the precise control of gene expression. Transcriptional repressor proteins associate with their target genes either directly through a DNA-binding domain or indirectly by interacting with other DNA-bound proteins. To inhibit transcription in a selective manner, a repressor protein can (1) mask a transcriptional activation domain, (2) block interaction of an activator with other components of the transcription machinery, or (3) displace an activator from the DNA. Furthermore, DNA response elements can exert allosteric effects on transcriptional regulators...
DNA Repair Mechanisms
Cells are constantly under threat from the cytotoxic and mutagenic effects of DNA damaging agents. Environmental DNA-damaging agents include UV light and ionizing radiation, as well as a variety of chemicals encountered in foodstuffs, or as air- and water-borne agents. Endogenous damaging agents include metabolites that can act as alkylating agents and the ROS (Reactive Oxygen Species) that arise during respiration. DNA repair enzymes continuously monitor chromosomes to correct damaged nucleotide residues generated by these exogenous and endogenous agents and exposure to carcinogens and cytotoxic compounds...
EGF Pathway
EGF (Epidermal Growth Factor) is a small 53 amino acid residue protein that is involved in normal cell growth, oncogenesis, and wound healing. This protein shows both strong sequential and functional homology with hTGF-Alpha (human type-Alpha Transforming Growth Factor), which is a competitor for EGF receptor sites. EGF binds to a specific high-affinity, low-capacity receptor on the surface of responsive cells known as EGFR (Epidermal growth factor receptor). EGFR is a member of the ErbB (Erythroblastic Leukemia Viral Oncogene Homolog) family receptors, a subfamily of four closely related receptor tyrosine kinases...
eNOS Signaling
NO (Nitric Oxide) is a short-lived free radical gas involved in diverse physiological and pathological processes. It is produced along with L-Citrulline by the oxidation of L-Arginine and catalyzed by three different isoforms of NOS (NO Synthase). Type-I nNOS (neuronal NOS) and Type-III eNOS (endothelial NOS) are constitutively expressed as latent enzymes and require a higher concentration of Ca2+ for the enzyme activity. In contrast, Type-II iNOS (inducible NOS) is Ca2+ independent because it s high affinity for Ca2+/Calm (Calmodulin) renders the enzyme active even at basal levels of intracellular Ca2+ (Ref.1 & 2). The ca...
Ephrin-EphR Signaling
In numerous processes that are vital for the development and maintenance of organism function, cells must communicate crucial information to respond appropriately to the changing environment. As such, RTKs (Receptor Tyrosine Kinases) are transmembrane proteins, which, on receiving an external stimulus, respond by transmitting a signal to the inside of the cell. Of all the RTKs that are found in the human genome, the Eph Receptor family and their ligands the Ephrins, constitutes the largest family....
Epithelial Tight Junctions
Epithelia in multicellular organisms constitute the frontier that separates the individual from the environment. Epithelia are sites of exchange as well as barriers, for the transit of ions and molecules from and into the organism. Epithelial cells achieve this by providing cellular borders that cover external and internal surfaces throughout the body. Complexes between adjacent cells include Gap Junctions, Desmosomes, Adherens Junctions (AJs) and Tight Junctions (TJs). Such junctions are quite essential for the modulation of paracellular permeability in various epithelia. Vertebrate epithelial cells exhibit Tight Junction...
ErbB Family Pathway
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) (Ref.1). Two of the family members, ErbB1 and E...
ERK Signaling
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...
Erythropoietin Pathway
Erythropoiesis is one major pathway by which a pluripotent hematopoietic stem cell gives rise to mature end stage cells. Erythropoietin (Epo) is a lineage-specific hematopoietic cell required for survival, proliferation and differentiation of committed erythroid progenitor cells. Its major effects are to promote erythroid differentiation and to initiate hemoglobin synthesis. Therefore, Epo has been identified as the major hormone required for erythropoiesis. Epo exerts its function through the EpoR (Epo Receptor), a member of the classI Cytokine receptor family (Ref.1). Following binding of Epo to its receptor, the recepto...
Estrogen Pathway
Estrogens play important roles in growth, development, reproduction, and maintenance of a diverse range of mammalian tissues. The physiological effects of estrogens are mediated by the intracellular ERs (Estrogen Receptors), which regulate transcription of target genes through binding to specific DNA target sequences. The ERs orchestrate both transcriptional and non-genomic functions in response to estrogens, xenoestrogens and signals emanating from growth factor signalling pathways. The pleiotropic and tissue-specific effects of estrogens are mediated by the differential expression of two distinct ER subtypes: ER-Alpha and ER-Beta...
Factors Promoting Cardiogenesis in Vertebrate
Heart is the first organ to form and function in the Embryo, and all subsequent events in the life of the organism depend on the Heart's ability to match its output with the organism's demands for Oxygen and nutrients. Abnormalities in Heart formation, the most common form of Human birth defects, affect nearly 1% of newborns, and their frequency in spontaneously aborted pregnancies is estimated to be tenfold higher. Heart development is an elaborate process requiring Cell specification, Cell differentiation, Cell migration, morphogenesis, and interactions among cells from several embryonic origins. The Heart is formed thro...
FAK1 Signaling
Engagement of integrin receptors with extracellular ligands gives rise to the formation of complex multi-protein structures that link the ECM (Extracellular Matrix) to the cytoplasmic actin cytoskeleton and signaling proteins including Talin, Alpha-actinin, Vinculin, Zyxin, Paxillin and FAK (Focal Adhesion Kinase). These adhesive complexes are dynamic, often heterogeneous structures, varying in size and organization, and signaling through these complexes and focal adhesions have been implicated in the regulation of a number of key cellular processes, including growth factor induced mitogenic signals, cell survival, cell pr...
Fas Signaling
Fas (also called Apo1 or CD95) is a death domain-containing member of the TNFR (Tumor Necrosis Factor Receptor) superfamily. It has a central role in the physiological regulation of Programmed Cell Death and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. Although the FasL (Fas Ligand)-Fas system has been appreciated mainly with respect to its death-inducing function, it also transduces proliferative and activating signals through pathways that are still poorly defined. The Fas Receptor induces an apoptotic signal by binding to....
FGF Pathway
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...
FLT3 Signaling
FLT3 (Fms-like Tyrosine Kinase-3), also known as FLK2 (Fetal Liver Kinase-2) and STK1 (human Stem Cell Kinase-1) was originally isolated as a hematopoietic progenitor cell-specific kinase, and belongs to the Class-III RTK (Receptor Tyrosine Kinase) family to which c-Fms, c-Kit, and the PDGFR (Platelet Derived Growth Factor Receptor) also belong (Ref.1). Normal expression of FLT3 is restricted to haemopoietic progenitor cells in the bone marrow, thymus and lymph nodes, but is also found on other tissues such as placenta, brain, cerebellum and gonads. Aberrantly expressed FLT3 is observed at high levels in a spectrum of hema...
Glucocorticoid Receptor Signaling
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
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...
Growth Hormone Signaling
Most aging individuals die from atherosclerosis, cancer, or dementia; but in the oldest old, loss of muscle strength resulting in frailty is the limiting factor for an individual's chances of living an independent life until death. Three hormonal systems show decreasing circulating hormone concentrations during normal aging: (i) estrogen (in menopause) and testosterone (in andropause), (ii) dehydroepiandrosterone and its sulphate (in adrenopause), and (iii) the growth hormone/IGF1 axis (in somatopause). Physical changes during aging have been considered physiologic, but there is evidence that some of these changes are related to this decline in hormonal activity...
GSK 3 Signaling
GSK3 (Glycogen Synthase Kinase-3) is a ubiquitously expressed, highly conserved serine/threonine protein kinase found in all eukaryotes. Identified originally as a regulator of glycogen metabolism, GSK3 acts as a downstream regulatory switch for numerous signaling pathways, including cellular responses to WNT, Growth Factors, Insulin, RTK (Receptor Tyrosine Kinases), Hedgehog pathways, and GPCR (G-Protein-Coupled Receptors) and is involved in a wide range of signal transduction cascades involving cellular processes, ranging from glycogen metabolism, cell development, gene transcription, protein translation to cytoskeletal organization...
Hedgehog
Controlled cell proliferation is a predominant theme in normal embryonic and post-embryonic development, and, in many instances, cell-type specification and cell proliferation are intimately coupled. Several secreted intercellular signaling proteins that behave as morphogens during pattern formation are also implicated in the regulation of the cell cycle. Hedgehogs (Hhs) are one such class of morphogens that regulate an enormous variety of developmental events in the fly and vertebrate embryo and plays a central role in several cancers....
HGF
HGF (Hepatocyte Growth Factor)/SF (Scatter Factor) is a mesenchymal- or stromal-derived multipotent heparan sulfate-binding and dermatan sulfate-binding pleiotropic polypeptide that mediates epithelial-mesenchymal interactions with mitogenic, motogenic and morphogenic activities towards many normal and neoplastic epithelial cells. Initially identified as a potent hepatotrophic factor responsible for vigorous regeneration of the liver, it has now become a well characterized multipotent cytokine with biological functions that reach far beyond the original identifications, operating in virtually every tissue of the body, the...
HIF1Alpha Pathway
The cellular response to O2 (oxygen) is a central process in animal cells and figures prominently in the pathophysiology of several diseases, including cancer, cardiovascular disease, and stroke. This process is coordinated by the HIF (Hypoxia-Inducible Factor) and its regulator, the pVHL (Von Hippel-Lindau tumor suppressor protein). HIF1 is a basic helix-loop-helix transcription factor that transactivates genes encoding proteins that participate in homeostatic responses to hypoxia. It induces expression of proteins controlling glucose metabolism, cell proliferation, and vascularization. Several genes...
Human Early Embryo Development
An Embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination. In Humans, it is called an Embryo from the moment of Fertilization until the end of the 8th week of gestational age, whereafter it is instead called a Fetus. In organisms that reproduce sexually, once a Sperm fertilizes an Egg cell, the result is a cell called the Zygote. In animals, the development of the Zygote into an embryo proceeds through specific recognizable stages of Blastula, Gastrula, and Organogenesis. Little is known about the specific genes that regul...
Human Embryonic Stem Cell Pluripotency
ESCs (Embryonic Stem Cells) are Pluripotent cells capable of differentiating into any cell type of the body. Only three species of Mammals have yielded long-term cultures of self-renewing ESCs- Mice, Monkeys, and Humans. Human ESCs are derived from Blastocysts, multicellular structures originating from four cleavages of fertilized oocytes. Isolated from the ICM (Inner Cell Mass) of Blastocysts, the ESCs retain properties of self-renewal and the potential to be committed and to differentiate toward most cell lineages. They are able to spontaneously give rise to different progenies of the three embryonic layers, namely, the...
IGF1R Signaling
Programmed cell death, a form of altruistic suicide is a genetically controlled means of cellular self-destruction that leads to dismantling and packaging of cell material for removal by phagocytosis. All cells possess the ability to undergo programmed cell death (otherwise known as apoptosis), and the process is essential for normal development to shape organs and tissues as well as to remove damaged cells. Although the cell may require de novo synthesis of some signaling molecules, the machinery for apoptosis is constantly present and may be rapidly activated. Therefore, the process of apoptosis needs tight regulation...
IL-10
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
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
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...
ILK Signaling
The ECM (Extracellular Matrix) provides the structural framework for the formation of tissues and organs. The ECM binds to substrate adhesion molecules on the surface of cells and influences various intracellular signaling pathways that regulate survival, proliferation, polarity and differentiation. The important families of adhesion molecules that bind to the ECM are the Integrins. Integrins consist of Alpha and Beta-subunits and are composed of large extracellular domains and relatively small cytoplasmic domains (Ref.1 & 2). Ligand binding activates signaling cascades that lead to the assembly of a multiprotein complex a...
Inhibition of Angiogenesis by TSP1
Cancer is a multistep process that includes deregulation of cell cycle, transformation, invasion of stroma, angiogenesis and metastasis. Angiogenesis is an essential component for tumor development regulated by both proangiogenic and antiangiogenic factors (Ref.1). It is a multi-step process that includes endothelial cell proliferation, migration, basement membrane degradation, and new lumen organization. Naturally occurring inhibitors of angiogenesis i.e., antiangiogenic factors are found in mammalian tissues, where they help maintain the quiescence of the normal vasculature. Thus, angiogenic inhibitors have been consider...
iNOS Signaling
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
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 ...
Integrin Signaling Pathway
Adhesive interactions between cells and ECM (Extracellular Matrix) proteins play a vital role in biological processes, including cell survival, growth, differentiation, migration, inflammatory responses, platelet aggregation, tissue repair and tumor invasion (Ref.4) and perturbing this coordination can lead to events such as malignant transformation. The major groups of proteins mediating these interactions are a family of cell surface receptors known as Integrins, named for their role in integrating the intracellular cytoskeleton with the ECM. The signals from these adhesion receptors are integrated with those originating from growth factor receptors...
Interferon Pathway
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...
Intracellular Calcium Signaling
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 (Ref.1). 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 bet...
IP3 Pathway
IP3 (Inositol 1,4,5-triphosphate), also known as a second messenger, is a molecule that functions to transfer a chemical signal received by the cell, such as from a hormone, neurotransmitters, growth factors and hypertrophic stimuli such as AngII (Angiotensin-II), Beta-adrenergic receptor agonists, and ET1 (Endothelin-1) to various signaling networks within the cell. IP3 is known to play a crucial role in initiating and propagating these messages; however, the precise mechanism of how IP3 relates to the next element in its signaling pathway, the calcium wave, remains highly controversial. The receptors for IP3, IP3R (IP3 Receptor) constitute a family...
JAK/STAT Pathway
Signaling pathways mediating the transduction of information between cells are essential for development, cellular differentiation and homeostasis. Their dysregulation is also frequently associated with human malignancies. The JAK (Janus tyrosine Kinase)-STAT (Signal Transducer and Activator of Transcription) pathway represents one such signaling cascade whose evolutionarily conserved roles include cell proliferation and haematopoiesis. JAK belongs to a family of non-receptor protein tyrosine kinases of approximately 130 kDa, comprising of JAK1, JAK2, JAK3 and TYK2 (non-receptor Protein Tyrosine Kinase-2). STATs are latent...
JNK Pathway
MAPKs (Mitogen-Activated Protein Kinases) are Serine-threonine protein Kinases that are activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus. MAPKs are expressed in multiple cell types including Cardiomyocytes, Vascular Endothelial cells, and Vascular Smooth Muscle Cells. Three major MAPKs include ERKs (Extracellular signal-Regulated Kinases), JNKs (c-Jun NH(2)-terminal protein Kinases), and p38 Kinases. Members of the JNK/SAPK (Stress-Activated Protein Kinase) family of MAPKs are strongly stimulated by numerous Environmental Stresses...
LDL Oxidation in Atherogenesis
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 world s 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
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
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 ....
Mismatch Repair
In all organisms, DNA repair processes are crucial to maintain the integrity of the genome through the generations. Many animals minimize the number of cell divisions and thus the chance to accumulate mutations from one to the next generation. The DNA MMR (Mismatch Repair) apparatus has an important function in stabilizing the genome, and the protein components of this system are highly conserved in all pro- and eukaryotic systems. The MMR system is responsible for the post-replicative repair of mismatches and small single stranded DNA loops, and it is critically involved in preventing recombination between homologous DNA...
Mitochondrial Apoptosis
Apoptosis is a naturally occurring process by which a cell is directed to Programmed Cell Death. Apoptosis is based on a genetic program that is an indispensable part of the development and function of an organism. In this process, cells that are no longer needed or that will be detrimental to an organism or tissue are disposed of in a neat and orderly manner; this prevents the development of an inflammatory response, which is often associated with Necrotic cell death. There are at least two broad pathways that lead to Apoptosis, an 'Extrinsic' and an 'Intrinsic' Pathway. In both pathways, signaling results in the activati...
mTOR Pathway
mTOR (Mammalian Target of Rapamycin) is a 289-kDa serine/threonine protein kinase and a member of the PIKK (Phosphatidylinositol 3-Kinase-related Kinase) family. The protein consists of a Catalytic Kinase domain, an FRB (FKBP12–Rapamycin Binding) domain, a putative Auto-inhibitory domain (Repressor domain) near the C-terminus and up to 20 tandemly repeated HEAT motifs at the Amino terminus, as well as FAT (FRAP-ATM-TRRAP) and FATC (FAT C-terminus) domains. The C-terminus of TOR is highly homologous to the catalytic domain of PI3K (Phosphatidylinositol 3-Kinase). TOR proteins are evolutionarily conserved from yeast...
Nanog in Mammalian ESC Pluripotency
ESCs (Embryonic stem cells) are Pluripotent cells derived from the ICM (Inner Cell Mass) of Blastocyst-stage embryos. These cells have two distinctive properties: an unlimited capacity for Self-renewal and Pluripotency. The capability for Self-renewal and the Pluripotency of ESCs seem to be under the control of multiple transcriptional factors, most common among them being Nanog (Nanog homeobox), Oct4 (Octamer Binding Transcription Factor-4) and SOX2 (SRY (Sex Determining Region-Y) Box-2). Functions of these transcription factors depend on the stage of development of a Pluripotent cell, indicating that these factors functi...
NF-KappaB Family Pathway
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
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
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...
Notch Signaling
The Notch signaling pathway is a fundamental signaling system used by neighboring cells to communicate with each other in order to assume their proper developmental role. Notch proteins are cell surface transmembrane-spanning receptors which mediate critically important cellular functions through direct cell-cell contact. Interaction between Notch and its proposed ligands initiates a signaling cascade that governs cell fate decisions such as differentiation, proliferation, and apoptosis in numerous tissue types. The core elements of the Notch signaling system include the Notch receptor...
P38 Signaling
Cellular responses to many external stimuli involve the activation of several types of MAPK (Mitogen-Activated Protein Kinase) signaling pathways. 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 so called ac...
p53 Signaling
p53 is a tumour suppressor protein that regulates the expression of a wide variety of genes involved in Apoptosis, Growth arrest, Inhibition of cell cycle progression, Differentiation and accelerated DNA repair or Senescence in response to Genotoxic or Cellular Stress. As a transcription factor, p53 is composed of an N-terminal Activation Domain, a central specific DNA Binding Domain, and a C-terminal Tetramerization Domain, followed by a Regulatory Domain rich in basic Amino acids. Having a short half-life, p53 is normally maintained at low levels in unstressed mammalian cells by continuous ubiquitylation and subsequent degradation by the 26S Proteasome...
PAK Pathway
PAKs (p21-Activated Protein Kinases) are a growing family of serine/threonine protein kinases, which are activated in response to extracellular signals and regulate cell shape and motility. PAKs regulate diverse cellular functions, including gene expression, cytoskeletal actin assembly, MAPK (Mitogen-Activated Protein Kinase) pathways, neurite outgrowth, cell cycle control, and cell apoptosis (Ref.1). The mammalian PAK family consists of six members, which can be divided into two subfamilies according to sequence homology. The first subfamily consists of PAK1 (Alpha-PAK), PAK2 (Gamma-PAK, PAK I) and PAK3 (Beta-PAK). PAK1 a...
PI3K Signaling in B-Lymphocyte
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...
PPAR Pathway
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)...
PTEN Pathway
Tumorigenesis is the result of abnormal activation of growth programs in the cells. Cancer cells escape normal growth control mechanisms as a consequence of activating mutations, or increased expression of one or more cellular protooncogenes, and/or inactivating mutations, or decreased expression of one or more tumor suppressor genes. Most oncogene and tumor suppressor gene products are components of signal transduction pathways that control cell cycle entry or exit, promote differentiation, sense DNA damage and initiate repair mechanisms, or regulate cell death programs....
Rac1 Pathway
To achieve strong adhesion to their neighbors and sustain stress and tension, epithelial cells develop many different specialized adhesive structures. Breakdown of these structures occurs during tumor progression with the development of a fibroblastic morphology characteristic of metastatic cells. Adhesion receptors of the Cadherin family have been implicated in these cellular processes, which play an important role in the development and maintenance of the differentiated epithelial phenotype during organogenesis and adult life. Cadherin-mediated adhesion requires the activity of the cytosolic proteins of the Rho subfamily...
RANK Signaling in Osteoclast
TNF (Tumor Necrosis Factor) and TNFR (Tumor Necrosis Factor Receptor) family proteins play important roles in the control of cell death, proliferation, autoimmunity, the function of immune cells, or the organogenesis of lymphoid organs. Recently, novel members of this large family have been identified that have critical functions in immunity and that couple lymphoid cells with other organ systems such as bone remodeling and mammary gland formation in pregnancy. Bone remodeling results from the coordinate action of bone resorption by osteoclasts and the formation of new bone by osteoblasts. Regulation of bone remodeling occ...
Ras Pathway
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...
Remodeling of Adherens Junctions
The intercellular Adherens Junctions (AJs) are specialized sub-apical structures that function as principle mediators of cell-cell adhesion. Their disassembly correlates with a loss of cell-cell contact and an acquisition of migratory potential. The Adherens Junctions have a crucial role both as sensors of extracellular stimuli and in regulating the dynamics of epithelial cell sheets or with neighboring cells. Cadherins, the Type-I transmembrane proteins of the Adherens Junctions, are principally responsible for homotypic cell-cell adhesion. E-Cadherin, which is present primarily in epithelia, is the best-characterized Cad...
Rho family GTPase
The Rho family of small GTP-binding proteins comprises a group of signaling molecules that are activated by a variety of Growth factors, Cytokines, Adhesion molecules, Hormones, Integrins, G-proteins and other biologically active substances and regulate a wide range of biological processes, including Reorganization of the Actin Cytoskeleton, Transcriptional Regulation, Vesicle Trafficking, Morphogenesis, Neutrophil activation, Phagocytosis and activation of the NADPH Oxidase, Mitogenesis, Apoptosis and Tumorigenesis. The mammalian Rho GTPase family currently consists of three subfamilies, Rho (RhoA, RhoB and RhoC), Rac (Ra...
RhoA Pathway
Rho is a member of the Ras superfamily of small GTP-binding proteins that play a central role in diverse biological processes such as Actin cytoskeleton organization, Microtubule dynamics, Gene transcription, Oncogenic transformation, Cell cycle progression, Adhesion and Epithelial wound repair. To date, 20 genes encoding different members of the Rho family have been identified in the human genome, and each one acts as a molecular switch to control distinct biochemical pathways. The mammalian Rho GTPase family currently consists of three subfamilies, Rho (RhoA, RhoB and RhoC), Rac (Rac1, Rac2 and Rac3) and CDC42 (Cell Divi...
RNAi Pathway
RNAi (RNA interference) is a cellular pathway of gene silencing in a sequence-specific manner at the mRNA (messenger RNA) level. The basic mechanism behind RNAi is the breaking of a dsRNA (double-stranded RNA) matching a specific gene sequence into short pieces of RNAs called siRNA (small interfering RNA). siRNAs are 21 23nt (nucleotide) dsRNA duplexes with symmetric 2-3nt 3' overhangs and 5'-phosphate and 3'-hydroxyl groups, which trigger the degradation of mRNA matching its sequence (Ref.1). Interference of gene expression by siRNA is now recognized as a naturally occurring biological strategy for silencing alleles durin...
Signaling in Gap Junction
Gap Junction (GJ) channels span two plasma membranes and are formed by the alignment of two hemichannels, each consisting of an oligomer of structural subunit proteins, called Cxs (Connexins). These junctional proteins constitute a multigene family whose members are distinguished according to their predicted molecular weight in kilodaltons. A Connexin structure consists of two extracellular loops (EL), four membrane-spanning domains ™, one cytoplasmic loop (CL), one N-terminal tail (NT), and one C-terminal tail (CT) (Ref.1 & 2). During intercellular channel formation, six Connexins oligomerize into a Connexon or hemicha...
SMAD Signaling Network
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
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...
SUMO Pathway
Covalent modifications of proteins, such as phosphorylation, acetylation and ubiquitylation, play an important role in most cellular processes because they can cause rapid changes in the activities of pre-existing proteins. This type of mechanism for regulating protein function is especially crucial in signal transduction pathways and in cell cycle. The Ubiquitin System is one of the major protein-modification systems required for the highly selective turnover of specific proteins in eukaryotic cells. These ubiquitin-like proteins modulate protein function in the cell through reversible post-translational modification, whi...
TCR Signaling
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
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
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
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
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...
TRAF Pathway
The structural and metabolic integrity of bone is maintained through the dynamic process of bone remodeling that results from the coordinate action of bone resorption and the formation of new bone by osteoblasts. Regulation of bone remodeling occurs through multiple mechanisms that ultimately converge on the interaction of osteoclasts or their precursors with osteoblasts and bone marrow stromal cells. Two key factors supplied by the stromal environment are CSF1 (Colony-Stimulating Factor-1) and the TNF family member, RANKL (Receptor Activator of Nuclear Factor-KappaB Ligand, also called TRANCE, ODF, OPGL). Signaling throug...
TRAIL
TRAIL (TNF-Related Apoptosis-Inducing Ligand) is a protein consisting of 281 amino acids. It is also called Apo2L. Five proteins, TRAILR1 (DR4), TRAILR2 (DR5/ TRICK2 or KILLER), TRAILR3 (DcR1/ TRID or LIT), TRAILR4 (DcR2 or TRUNDD), and Opg (Osteoprotegerin), have been identified as TRAIL receptors (Ref.1). Both TRAILR1 and TRAILR2 contain the functional DD (Death Domain), capable of inducing apoptosis. The other three receptors DcR1, DcR2 and Opg serve as 'decoy' receptors. These three receptors can bind to TRAIL, but cannot induce apoptosis. DcR1 is a glycosylphosphatidylinositol-anchored cell surface protein, which cont...
Transcription of mRNA
Transcription is the process through which a DNA sequence is enzymatically copied by an RNA polymerase to produce a complementary RNA. Transcription can also be defined as a process that transcribes genetic information from DNA into RNA. In eukaryotes, it takes place in the nucleus, mitochondria and chloroplast. Transcription is performed by DNA-directed RNA Polymerases. Unlike DNA Polymerases, RNA Polymerases do not need a primer to start the reaction. While Bacteria contain only 1 RNA Polymerase, there are 3 different RNA polymerases in eukaryotic cells, which catalyzes the synthesis of three types of RNA...
Transcriptional Regulatory Network in Embryonic Stem Cell
Stem Cells are undifferentiated cells that can give rise to several lineages of differentiated cell types. They are the founder cells for every organ, tissue and cell in the body. Stem cells are characterized by the ability to self-renew and maintain Pluripotency. These features allow Stem Cells to fulfill their multiple functions, namely to provide enough cells during organogenesis, to control tissue homeostasis and, in addition, to ensure regeneration and repair. ESCs (Embryonic Stem Cells) are derived from the ICM (Inner Cell Mass) of the developing Blastocysts, multicellular structures originating from four (Human) to...
Transendothelial Migration of Leukocytes
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...
Ubiquitin-Proteasome Dependent Proteolysis
The Proper functioning of a cell requires careful control of the levels of important structural proteins, enzymes, and regulatory proteins. Protein molecules are continuously synthesised and degraded in all living organisms. The concentration of individual cellular proteins is determined by a balance between the rates of synthesis and degradation, which in turn are controlled by a series of regulated biochemical mechanisms. Differences in the rates of protein synthesis and breakdown result in cellular and tissue atrophy (loss of proteins from cells) and hypertrophy (increase in protein content of cells). Precise control of...
VEGF Pathway
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
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...
