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Afferent Pathways definition: Nerve structures through which impulses are conducted from a peripheral part toward a nerve center.
Afferent Pathway definition: Nerve structures through which impulses are conducted from a peripheral part toward a nerve center. (MeSH)
auditory pathway definition: cochlear nuclei give rise to two bundles, the trapezoid body and dorsal acoustic stria, which rejoin as the lateral lemniscus and continue via the inferior colliculus to the auditory cortex.
Complement Pathway, Alternative definition: Complement activation initiated by the interaction of microbial ANTIGENS with COMPLEMENT C3B. When COMPLEMENT FACTOR B binds to the membrane-bound C3b, COMPLEMENT FACTOR D cleaves it to form alternative C3 CONVERTASE (C3BBB) which, stabilized by COMPLEMENT FACTOR P, is able to cleave multiple COMPLEMENT C3 to form alternative C5 CONVERTASE (C3BBB3B) leading to cleavage of COMPLEMENT C5 and the assembly of COMPLEMENT MEMBRANE ATTACK COMPLEX.
complement activation, alternative pathway definition: Any process involved in the activation of any of the steps of the alternative pathway of the complement cascade which allows for the direct killing of microbes and the regulation of other immune processes. [GOC:add, ISBN:0781735149 "Fundamental Immunology"]
alternative complement pathway definition: complement activation sequence initiated by the activation of complement factor C3, which is triggered by the interaction of microbial polysaccharides and properdin without participation of an antigen-antibody reaction.
Alternative Complement Pathway definition: The complement system of plasma proteins is an important part of the immune system that forms a cascade of factors that lyses foreign cells. There are two branches of the complement system, the classical pathway that is initiated by antibody-antigen complexes on a cell and the alternative pathway that is antibody independent. The ultimate result in either pathway is the creation of the membrane attack complex, a large pore in the cell membrane that results in cell lysis. The alternative pathway starts with the spontaneous conversion of C3 to an active protease. C3 contains a thioester group that is spontaneously hydrolyzed at a slow rate to create C3(H2O). From there, binding of factor B (Fb) and activation by factor D (Fd) cleaves factor B to create the active protease C3 convertase (AP convertase). This enzyme cleaves C3 to form C3b, which can go on to form a C5 activating convertase. At this point the alternative pathway proceeds in the same manner as the classical pathway, recruiting additional complement factors (C6, C7, C8 and C9) to ultimately form the membrane attack complex and lyse the associated cell. One question about the alternative pathway is how the spontaneous activation of C3 in plasma leads to the lysis of specific cells in the absence of antibody on the cell surface. Active C3b binds to the cell surface, particularly to complement activators like cell wall components and lipopolysaccharide. A constant low level of spontaneous C3b formation ensures that C3b can bind to invading cells and trigger the rest of the alternative complement pathway to lyse the cells even in the absence of an antibody response. The constant low level of C3b activation and potential activation of the alternative pathway is kept in check by a natural damper, factor H and factor I. Factors H and I in plasma inactivate C3b enzyme in solution. Factors H and I cannot inactivate C3b on the cell surface due to protection by properdin, ensuring that the alternative pathway is primarily inactive in plasma and specifically activated on the surface of invading. (BioCarta)
Efferent Pathways definition: Nerve structures through which impulses are conducted from a nerve center toward a peripheral site. Such impulses are conducted via efferent neurons (NEURONS, EFFERENT), such as MOTOR NEURONS, autonomic neurons, and hypophyseal neurons.
Efferent Pathway definition: Nerve structures through which impulses are conducted from a nerve center toward a peripheral site. (MeSH)
Neural Pathways definition: Neural tracts connecting one part of the nervous system with another.
Neural Pathway definition: Neural tracts connecting one part of the nervous system with another. (MeSH)
Olfactory Pathways definition: Set of nerve fibers conducting impulses from olfactory receptors to the cerebral cortex. It includes the OLFACTORY NERVE; OLFACTORY BULB; olfactory tract, olfactory tubercle, anterior perforated substance, and olfactory cortex. The term rhinencephalon is restricted to structures in the CNS receiving fibers from the olfactory bulb.
pentose phosphate shunt definition: pathway of hexose oxidation in which glucose-6-phosphate undergoes two successive oxidations by NADP, the final one being an oxidative decarboxylation to form a pentose phosphate.
pentose-phosphate shunt definition: The process by which glucose is oxidized, coupled to NADPH synthesis. Glucose 6-P is oxidized with the formation of carbon dioxide (CO2), ribulose 5-phosphate and reduced NADP; ribulose 5-P then enters a series of reactions interconverting sugar phosphates. The pentose phosphate pathway is a major source of reducing equivalents for biosynthesis reactions and is also important for the conversion of hexoses to pentoses. [ISBN:0198506732 "Oxford Dictionary of Biochemistry and Molecular Biology", MetaCyc:PENTOSE-P-PWY]
Pentose Phosphate Pathway definition: An oxidative decarboxylation process that converts GLUCOSE-6-PHOSPHATE to D-ribose-5-phosphate via 6-phosphogluconate. The pentose product is used in the biosynthesis of NUCLEIC ACIDS. The generated energy is stored in the form of NADPH. This pathway is prominent in tissues which are active in the synthesis of FATTY ACIDS and STEROIDS.
Visual Pathways definition: Set of cell bodies and nerve fibers conducting impulses from the eyes to the cerebral cortex. It includes the RETINA; OPTIC NERVE; optic tract; and geniculocalcarine tract.
visual pathway definition: sensory pathway for sight, conducting impulses from the photoreceptors to the cerebral cortex by way of the optic nerve, optic tract, and optic radiation.
Apoptosis definition: One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.
apoptosis definition: (ap-o-TOE-sis) A normal series of events in a cell that leads to its death.
apoptosis definition: A form of programmed cell death that begins when a cell receives internal or external signals that trigger the activity of proteolytic caspases, proceeds through a series of characteristic stages typically including rounding-up of the cell, retraction of pseudopodes, reduction of cellular volume (pyknosis), chromatin condensation, nuclear fragmentation (karyorrhexis), and plasma membrane blebbing (but maintenance of its integrity until the final stages of the process), and ends with the death of the cell. [GOC:go_curators, ISBN:0198506732 "Oxford Dictionary of Biochemistry and Molecular Biology", PMID:18846107]
programmed cell death definition: Cell death resulting from activation of endogenous cellular processes. [GOC:lr]
apoptosis definition: active process of selective destruction of differentiated cells in multicellular organisms; important in ontogenesis, tumorigenesis, tissue turnover, lymphocyte selection and function, hormone-induced atrophy, etc.; apoptosis is a specific mechanism involving self- fragmentation of chromatin.
Apoptosis definition: An active process of selective destruction of differentiated cells in multicellular organisms, apoptosis is one of two mechanisms by which cell death occurs (the other being necrosis, a pathological process). Important in ontogenesis, tumorigenesis, tissue turnover, lymphocyte selection and function, hormone-induced atrophy, etc., it serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Apoptosis is responsible for physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, including chromatin cleavage at regularly spaced sites and endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites.
Autonomic Pathways definition: Nerves and plexuses of the autonomic nervous system. The central nervous system structures which regulate the autonomic nervous system are not included.
Clinical Pathway definition: A defined set of diagnostic tests, treatments, and other interventions (including palliative care) for different types and stages of cancer.
Critical Pathways definition: Schedules of medical and nursing procedures, including diagnostic tests, medications, and consultations designed to effect an efficient, coordinated program of treatment. (From Mosby's Medical, Nursing & Allied Health Dictionary, 4th ed)
Perforant Pathway definition: A pathway of fibers that originates in the lateral part of the ENTORHINAL CORTEX, perforates the SUBICULUM of the HIPPOCAMPUS, and runs into the stratum moleculare of the hippocampus, where these fibers synapse with others that go to the DENTATE GYRUS where the pathway terminates. It is also known as the perforating fasciculus.
Perforant Pathway definition: A pathway of fibers originating in the lateral part of the entorhinal area, perforating the subiculum of the hippocampus, and running into the stratum moleculare of the hippocampus, where these fibers synapse with others that go to the dentate gyrus. It is also called the perforating fasciculus. (MeSH)
Pathway Analysis definition: Elucidation of anabolic and catabolic pathways using labelled molecules or precursors. (NCI/OSP)
lysine biosynthetic process via diaminopimelate definition: The chemical reactions and pathways resulting in the formation of lysine, via the intermediate diaminopimelate. [GOC:go_curators]
2,5-dihydroxypyridine catabolic process to fumarate definition: The chemical reactions and pathways resulting in the breakdown of 2,5-dihydroxypyridine to form fumarate. 2,5-dihydroxypyridine is dioxygenated to give maleamate and formate; the maleamate from this reaction is then converted to maleate, which is then isomerized to fumurate. [MetaCyc:PWY-722]
glucose catabolic process to lactate via pyruvate definition: The anaerobic enzymatic chemical reactions and pathways resulting in the breakdown of glucose to lactate, via pyruvate, yielding energy in the form of adenosine triphosphate (ATP). [GOC:jl, http://dwb.unl.edu/]
lactate fermentation to propionate and acetate definition: The anaerobic enzymatic conversion of lactate to propionate, concomitant with the oxidation of lactate to acetate and CO2 and yielding energy in the form of adenosine triphosphate (ATP). [GOC:jl, MetaCyc:PROPFERM-PWY]
glucose catabolic process to D-lactate and ethanol definition: The anaerobic chemical reactions and pathways resulting in the enzymatic breakdown of D-glucose to D-lactate and ethanol, yielding energy in the form of adenosine triphosphate (ATP) at the rate of one ATP per glucose molecule. [GOC:jl, MetaCyc:P122-PWY]
glucose catabolic process to lactate and acetate definition: The anaerobic chemical reactions and pathways resulting in the breakdown of glucose to lactate and acetate, yielding energy in the form of ATP. [MetaCyc:P124-PWY]
denitrification pathway definition: The reduction of nitrate to dinitrogen by four reactions; each intermediate is transformed to the next lower oxidation state; also part of cellular bioenergetics; the nitrogen compounds can serve as terminal acceptors for electron transport phosphorylation in place of oxygen. [MetaCyc:DENITRIFICATION-PWY]
mRNA polyadenylation definition: The enzymatic addition of a sequence of 40-200 adenylyl residues at the 3' end of a eukaryotic mRNA primary transcript. [ISBN:0198506732 "Oxford Dictionary of Biochemistry and Molecular Biology"]
Polyadenylation Pathway definition: Gene expression requires the coordination and integration of multiple processes, including transcription, splicing, polyadenylation, nucleocytoplasmic export, and translation of mRNAs. Posttranscriptional addition of poly (A) to the 3' end of mRNA is an important process conserved from bacteria to humans. In eukaryotes, polyadenylation is essential for the stability of many mRNAs and also influences the efficiency of translation. Most histone-mRNAs and all snRNAs (except U6), however are not polyadenylated. The mature mRNA moves to the nuclear surface and is exported through nuclear pores. (BioCarta)
Secretory Pathway definition: A series of sequential intracellular steps involved in the transport of proteins (such as hormones and enzymes) from the site of synthesis to outside the cell. The pathway involves membrane-bound compartments through which the newly synthesized proteins undergo POST-TRANSLATIONAL MODIFICATIONS, packaging, storage, or transportation to the PLASMA MEMBRANE for secretion.
secretory pathway definition: OBSOLETE. The pathway along which proteins and other substances are moved around and out of the cell. After synthesis on the ribosomes of the endoplasmic reticulum (ER), completed polypeptide chains are moved to the Golgi complex and subsequently sorted to various destinations. Proteins synthesized and sorted in the secretory pathway include not only those that are secreted from the cell but also enzymes and other resident proteins in the lumen of the ER, Golgi, and lysosomes as well as integral proteins in the membranes of these organelles and the plasma membrane. [ISBN:0716731363]
Metabolic Pathway definition: An elaboration of the known steps and interactions for the metabolism of a compound.
complement pathway definition: classical complement pathway is the sequential activation of complement, initiated by antigen-antibody complex and the binding of complement factor C1q to the Fc region of the antibody; alternative complement pathway is the complement activation sequence initiated by the activation of complement factor C3, which is triggered by the interaction of microbial polysaccharides and properdin without participation of an antigen-antibody reaction.
Complement Pathway definition: The complement pathway consists of a series of over thirty proteins in plasma that are part of the immune response. Activation of the complement system lyses bacterial cells, forms chemotactic peptides (C3a and C5a) attracting immune cells, and increases phagocytotic clearance of infecting cells. Complement can also increase the permeability of vascular walls and cause inflammation. Most complement proteins exist in plasma as inactive precursors that cleave and activate each other in a proteolytic cascade in response to three different mechanisms by which the complement system is activated, the classical pathway, the alternative pathway and the lectin-induced pathway. These three systems are distinct in the initiation of the proteolytic cascade but share most of their components and all three converge in the creation of a C3 convertase that cleaves the C3 complement protein, leading ultimately to the formation of the membrane attack complex, MAC, a pore causing lysis of cells. The classical pathway is activated by the recognition of foreign cells by antibodies bound to the surface of the cells. The alternative and lectin-induced pathways are both antibody independent. Proteolysis is triggered in the alternative pathway by the spontaneous activation of C3 convertase from C3 and is triggered in the lectin-induced pathway by the recognition of carbohydrates on the bacterial cell surface by mannan-binding protein, Mbp. In addition to providing a key part of the response to bacterial infection, the complement system can be involved in the response to fungi, viruses and protists. While activation of the complement system is a key part of the immune system, it must also be kept in check to prevent inappropriate or exaggerated responses. Twelve different proteins have been identified that inhibit complement activation to control the system, including Factor H, Factor I and C1 inhibitor. Deficiencies in components of the complement system have been identified in humans that cause a variety of immune related disorders. C3 deficiency is associated with recurrent bacterial infections, while a lack of C2 can cause antibody-antigen complexes to accumulate and cause the autoimmune disorder systemic lupus erythematosus. People lacking C1 inhibitor have also been identified and found to be prone to uncontrolled complement activation and dangerous swelling through production of C3a and C5a anaphylotoxins. (BioCarta)
Acetaminophen Pathway definition: Acetaminophen is one of the world's most commonly used drugs, used for the treatment of pain and fever. Like other NSAIDs (non-steroidal anti-inflammatory drugs), acetaminophen has a unique activity profile based in part on its action at its molecular targets, the cyclooxygenase enzymes that produce prostaglandins responsible for pain, fever and inflammation. Until very recently, only two Cox enzymes, Cox-1 and Cox-2, were known to be targets of NSAIDS. Cox-1 is expressed in a constitutive manner throughout most tissues, and plays an essential role in maintaining the integrity of the stomach mucosal lining. Cox-2 is an inducible enzyme whose expression is induced by inflammation. NSAIDS selective for Cox-2 have been developed to avoid the development of ulcers by some non-selective NSAIDs, including aspirin. While these two isoforms were sufficient to account for most NSAIDs pharmacology, the actions of acetaminophen remained hard to explain on the basis of inhibiting Cox-1 and Cox-2 alone, such as its efficacy at reducing pain and fever but lack of anti-inflammatory effects. A novel Cox enzyme isoform encoded by the Cox-1 gene, Cox-3, contains an additional 30-34 amino acids and is expressed selectively in the brain. This insertion alters the pharmacology of the Cox enzyme, making Cox-3 sensitive to selective inhibition by acetaminophen and other drugs that reduce pain and fever but have weak anti-inflammatory activity, explaining the pharmacology of these drugs. Another characteristic of acetaminophen is its liver toxicity when taken at high doses. The target of this toxicity has also been recently been revealed. The nuclear receptor CAR is activated by many different exogenous compounds, including acetaminophen, inducing expression of three cytochrome P450 enzymes that transform acetaminophen into NAPQI, a reactive and toxic metabolite. Blocking CAR activation with an antagonist protects against acetaminophen liver toxicity, suggesting a strategy to treat acetaminophen toxicity. (BioCarta)
Agrin Pathway definition: The heparan sulphate proteoglycan agrin is well known as the key assembly factor of postsynaptic differentiation at the neuromuscular junction (NMJ), but recent data suggest it also plays a direct role in the organization of the cytoskeleton in the skeletal muscle. Signaling through muscle-specific proteins such as muscle specific kinase (MuSK) and or acetylcholine receptor (AchRs)/rapsyn, agrin can activate ubiquitously expressed Rac, Cdc42, and p21-activated kinase (PAK) that are involved in actin polymerization. Agrin also engages signaling pathways of several potent oncogenes (i.e., SFK, ErbB receptors, and cortactin). (BioCarta)
Angiogenesis Pathway definition: Vascular endothelial growth factor (VEGF) plays a key role in physiological blood vessel formation and pathological angiogenesis such as tumor growth and ischemic diseases. Hypoxia is a potent inducer of VEGF in vitro. The increase in secreted biologically active VEGF protein from cells exposed to hypoxia is partly because of an increased transcription rate, mediated by binding of hypoxia-inducible factor-1 (HIF1) to a hypoxia responsive element in the 5'-flanking region of the VEGF gene. bHLH-PAS transcription factor that interacts with the Ah receptor nuclear translocator (Arnt), and its predicted amino acid sequence, exhibits significant similarity to the hypoxia-inducible factor 1alpha (HIF1a) product. HLF mRNA expression is closely correlated with that of VEGF mRNA. The high expression level of HLF mRNA in the O2 delivery system of developing embryos and adult organs suggests that in a normoxic state, HLF regulates gene expression of VEGF, various glycolytic enzymes, and others driven by the HRE sequence, and may be involved in development of blood vessels and the tubular system of lung. VEGF expression is dramatically induced by hypoxia due in large part to an increase in the stability of its mRNA. HuR binds with high affinity and specificity to the VRS element that regulates VEGF mRNA stability by hypoxia. In addition, an internal ribosome entry site (IRES) ensures efficient translation of VEGF mRNA even under hypoxia. The VHL tumor suppressor (von Hippel-Lindau) regulates also VEGF expression at a post-transcriptional level. The secreted VEGF is a major angiogenic factor that regulates multiple endothelial cell functions, including mitogenesis. Cellular and circulating levels of VEGF are elevated in hematologic malignancies and are adversely associated with prognosis. Angiogenesis is a very complex, tightly regulated, multistep process, the targeting of which may well prove useful in the creation of novel therapeutic agents. Current approaches being investigated include the inhibition of angiogenesis stimulants (e.g., VEGF), or their receptors, blockade of endothelial cell activation, inhibition of matrix metalloproteinases, and inhibition of tumor vasculature. Preclinical, phase I, and phase II studies of both monoclonal antibodies to VEGF and blockers of the VEGF receptor tyrosine kinase pathway indicate that these agents are safe and offer potential clinical utility in patients with hematologic malignancies. (BioCarta)
Botulin Pathway definition: The neuromuscular junction communicates action potentials from motor neurons across a synapse to skeletal muscle. When an action impulse arrives at the neuromuscular junction, the entry of calcium through voltage-gated calcium channels causes synaptic vesicles to fuse with the presynaptic plasma membrane and release the neurotransmitter acetylcholine into the synaptic cleft. Acetylcholine diffuses across the cleft and binds to muscle acetylcholine receptors, causing depolarization and an action potential that travels throughout the length of the muscle cell triggering muscle contraction. The release of neurotransmitter at the synapse involves the fusion of synaptic vesicles with the neuronal plasma membrane and requires several proteins that act together to form a synaptic fusion complex. These proteins, collectively called SNARE proteins, include SNAP-25, syntaxin, and synaptobrevin. Homologs of these proteins are also involved in membrane fusion in other aspects of vesicle trafficking. Synaptobrevin (also called VAMP2) is localized at the synaptic vesicle membrane, while SNAP-25 and syntaxin are associated with the plasma membrane. Calcium release causes the formation of a complex, bringing the synaptic vesicle in close proximity with the plasma membrane and allowing fusion of the membranes. Biological toxins often disrupt nervous function, particularly the action of motor neurons. Botulinum toxin, synthesized by the bacteria Clostridium botulinum, is one of the most potent toxins known and acts by blocking neurotransmitter release at the neuromuscular junction. Botulinum toxin is a protein composed of two subunits joined by a disulfide bond, a 100 kD heavy subunit and a 50 kD light subunit that is a protease. There are seven serotypes of botulinum with distinct toxins. Tetanus toxin is similar in structure and in mechanism of action to botulinum toxin. The toxins can be absorbed in the intestine to travel in the blood to its site of action, at the neuromuscular junction. At the synapse botulinum toxin binds to the presynaptic membrane, and large subunit mediates internalization into the neuron through endocytosis. Once inside the neuron, the light chain is translocated across the vesicular membrane to act as a protease on cytoplasmic substrates. The targets of the toxin protease include the components of the synaptic fusion complex. Tetanus toxin and botulinum B, D, F and G toxins degrade synaptobrevin, while botulinum A, C and E toxins cleave SNAP-25. Syntaxin is also targeted by serotype C toxin. Destruction of these proteins by botulinum toxin prevents vesicular fusion in response to action potentials, blocking the release of acetylcholine. This blockade of communication between the nervous system and skeletal muscle can cause paralysis and can lead to death if the paralysis is severe enough to prevent breathing. In addition to acting as a toxin during botulism infection, botulinum toxin is also now being used as a pharmaceutical. Careful administration of very small doses of toxin can restrict its action locally to reduce overactive muscles, such as those involved in twitching of the eyes. Relaxing the muscles around the eyes can also reduce wrinkles in the eye region, leading to cosmetic use of this potent bacterial toxin. The potency of botulinum toxin has also caused concern that it could be used as a biological weapon, creating interest in the identification of inhibitors of this toxin. (Biocarta)
CFTR Pathway definition: The defects in cAMP-regulated chloride channel CTFR are believed to be the major cause for cystic fibrosis. Regulation of CFTR protein by the surface receptor beta adrenergic receptor is mediated through the ezrin/radixin/moesin binding phosphoprotein 50 (EBP50), which binds both the C-termini CFTR and b2AR through their PDZ binding motifs. In the resting state, CFTR, b2AR, and EBP50 exist as a macromolecular complex on the apical surface of epithelial cells. Upon agonist activation of the b2AR, the adenylate cyclase is stimulated through the G protein pathway, leading to an increase in cAMP. The elevated concentration of cAMP activates PKA, which is anchored near CFTR via interaction with Ezrin. The phosphorylation of CFTR by PKA disrupts the complex and leads to compartmentalized and specific signaling of the channel. (BioCarta)
CTCF Pathway definition: CTCF is central to signaling pathways in immature B cells elicited by cross-linking the Ig BCR and stimulation with TGF. Both stimuli result in induction of cell cycle arrest and apoptosis. BCR ligation stimulates a transient induction of MYC that leads to high level CTCF expression and feedback suppression of MYC transcription. BCR ligation also activates PTEN opposing PI3K activation of MYC. Pharmacologic inactivation of PI3K or mTOR/FRAP results in suppression of S6K resulting in activation of CTCF and suppression of MYC. CTCF activation induces transcriptional activation of p19ARF, with its downstream consequences, and of p27. Growth arrest is occasioned by co-expression of p21 and p27 and inhibition of MYC. CTCF, is a multivalent DNA-sequence binder whose specificity is mediated by different sets of zinc finger (ZF) proteins. (BioCarta)
Dicer Pathway definition: The degradation of endogenous mRNA in a sequence-specific manner can be induced by dsRNA [RNA interference (RNAi)], antisense transcription, or viral infection. In the current model for posttranscriptional gene silencing by RNAi, the ribonuclease III like enzyme Dicer processes dsRNA into small fragments (siRNA) of 21-25 nts. The siRNA is incorporated into the RNA-induced silencing complex (RISC), which targets and degrades the homologous mRNA. Most of the proteins in the RISC (with the exception of Ago2 and Dicer have not been identified) but likely contain endonuclease, helicase, exonuclease and homology scanning activity. (BioCarta)
Glycolysis Pathway definition: In glycolysis, the six-carbon sugar glucose is oxidized and split in two halves, to create two molecules of pyruvate (3 carbons each) from each molecule of glucose. Along the way, the cell extracts a relatively small amount of energy from glucose in the form of ATP, 2 ATP molecules collected for each glucose molecule that starts down the glycolytic path. The pyruvate produced has one of three metabolic fates, to either become acetyl-CoA, ethanol, or lactate. When oxygen is available, the pyruvate can be converted to acetyl-CoA and enter the Krebs Cycle, where the acetyl-CoA will be completely oxidized and generate ATP through oxidative phosphorylation. Fermentation is much less efficient than oxidative phosphorylation in making ATP, creating only 2 ATP per glucose while oxidative phosphorylation creates 36 ATP per glucose in mammalian cells. Oxidative phosphorylation does not work in the absence of oxygen, however, and in the absence of oxygen glycolysis is forced to a halt due to a lack of NAD+, unless NAD+ is regenerated through fermentation. In mammalian muscle, strenuous exertion can create conditions in which oxygen is consumed faster than blood can provide it, forcing the muscle to use fermentation and create lactic acid; it is the lactic acid that makes your muscles sore after a workout. There are ten enzymes that catalyze the steps in glycolysis that convert glucose into pyruvate, and the entire pathway is located in the cytoplasm of eukaryotic cells. The activity of the pathway is regulated at key steps to ensure that glucose consumption and energy production match the needs of the cell. The steps along the pathway each involve a change in the free energy of the products and reactants, and as long as the overall change in free energy is negative, the reaction continues forward, like water flowing down hill to its lowest energy point. The key steps in the regulation of glycolysis, or any pathway, are those that catalyze the rate-limiting, irreversible steps along the pathway. In glycolysis in mammals, the key regulatory enzyme is phosphofructokinase, which catalyzes the rate-limiting committed step. Phosphofructokinase is activated by AMP and inhibited by ATP, among other regulatory mechanisms. Thus, when ATP is low (and AMP is high), phosphofructokinase will be activated and generate more ATP. Similarly, when ATP is abundant, phosphofructokinase will be inhibited to prevent wasting glucose on making energy when it is not needed. Failure to provide energy can have lethal consequences for cells - the absence of oxygen caused by a stroke or a heart attack that prevents ATP generation can have lethal consequences for the cells involved. Cancer cells often generate energy through glycolytic fermentation more than oxidative phosphorylation, suggesting that manipulation of metabolism may provide a therapeutic strategy. Well known glycolytic enzymes such as glyceraldehyde-3-phosphate dehydrogenase may play roles in other cellular processes such as apoptosis. (BioCarta)
HOP Pathway definition: Homeodomain transcription factors comprise a large family of DNA binding factors that regulate transcription and development. Many homeodomain genes arranged in genomic clusters determine anterior-posterior patterning, while others determine the fate of cells in specific tissues. The proliferation of cardiac myocytes and their differentiation early in development are dependent on the coordinate expression and action of serum response factor (SRF), GATA4 and the homeodomain factor Nkx2-5. All three of these factors are expressed in developing cardiomyocytes and induce expression of cardiac genes. Disruption of the Nkx2-5 gene in mice leads to embryonic lethality and defective cardiac development. SRF also plays a duel role in cardiac development, influencing both cardiomyocyte proliferation and differentiation depending on the stage and other signals that are present. In addition, the Hop (Homeodomain Only Protein) gene encodes a factor expressed early in cardiac development that is involved in cardiac differentiation. Hop inactivation in vertebrates leads to severe defects in cardiac development, acting downstream of Nkx2-5. Cardiac cells from mice lacking the Hop gene fail to exit the cell cycle in the normal manner, continuing to proliferate past the normal developmental stage. Many of the genes disregulated in the absence of Hop are involved in the cell cycle and are also targets of SRF. Although Hop is a homeodomain protein, it lacks a DNA-binding domain indicating that it must not regulate gene expression directly. Hop appears to regulate the expression of cardiac genes by binding to SRF and blocking DNA binding of SRF. The sequestration of SRF by Hop blocks the activation of cardiac genes, preventing normal cardiac development. The influence of Hop on the opposing processes of cardiomyocyte differentiation and proliferation reflect the interaction of Hop with SRF and the duel role SRF plays. In early cardiac development, Hop opposes differentiation induction by SRF, while at later stages Hop opposes the proliferation induced by SRF. (BioCarta)
Hematopoiesis Pathway definition: The process of hematopoiesis is regulated by various cytokines. The combination of cytokines stimulates the proliferation and/or differentiation of the various hematopoietic cell types. Bone marrow stromal cells are the major source of hematopoietic cytokines in the non-infectious state. In the presence of infection, cytokines produced by activated macrophages and TH cells induce hematopoietic activity. The induction by cytokines results in rapid expansion of the population of white blood cells to fight infection. (BioCarta)
Hypoxia Pathway definition: Hypoxic stress, like DNA damage, induces p53 protein accumulation and p53-dependent apoptosis in oncogenically transformed cells. Unlike DNA damage, hypoxia does not induce p53-dependent cell cycle arrest, suggesting that p53 activity is differentially regulated by these two stresses. Hypoxia induces p53 protein accumulation, but in contrast to DNA damage, hypoxia fails to induce endogenous downstream p53 effector mRNAs and proteins, such as p21, Bax, CIP1, WAF1, etc. Hypoxia does not inhibit the induction of p53 target genes by ionizing radiation, indicating that p53-dependent transactivation requires a DNA damage-inducible signal that is lacking under hypoxic treatment alone. The phosphatidylinositol 3-OH-kinase-Akt pathway inhibits p53-mediated transcription and apoptosis. Mdm2, a ubiquitin ligase for p53, plays a central role in regulation of the stability of p53 and serves as a good substrate for Akt. Mdm-2 targets the p53 tumor suppressor for ubiquitin-dependent degradation by the proteasome, but, in addition, the p53 transcription factor induces Mdm-2, thus, establishing a feedback loop. Hypoxia or DNA damage by abrogating binding of HIF-1 with VHL and p53 with Mdm-2, respectively, leads to stabilization and accumulation of transcriptionally active HIF-1 and p53. At the molecular level, DNA damage induces the interaction of p53 with the transcriptional activator p300 as well as with the transcriptional corepressor mSin3A. In contrast, hypoxia primarily induces an interaction of p53 with mSin3A, but not with p300. (BioCarta)
IL2RB Pathway definition: The IL-2 receptor is a key component of immune signaling and is required for the activation, proliferation, and survival of T cells. This receptor is composed of three polypeptide chains, the alpha, beta, and gamma chains. The IL-2 receptor gamma chain is a common component for several other cytokine receptors, including IL-4, IL-7, IL-9 and IL-15. The IL-2 receptor beta chain is essential for IL-2 signaling and is also a component of the IL-15 receptor complex. The polypeptides of the IL-2 receptor do not themselves have intrinsic catalytic activity, but interact with cytoplasmic signaling proteins to transduce signals. Different regions of the cytoplasmic domain of the IL-2 receptor beta chain interact and couple with distinct signaling pathways and cellular responses. JAK1 associates with the beta chain and JAK3 with the gamma chain. Binding of IL-2 induces heterodimerization of receptor subunits, and activation of JAK kinase activity. Tyrosine residues in the beta chain cytoplasmic domain are phosphorylated during activation, recruiting other factors to the phosphorylated tyrosine residues through src homology 2 (SH2) domains. The adaptor protein Shc binds to phosphorylated tyrosine 338 of the beta chain. When bound, Shc is phosphorylated and couples through Grb2 and Sos-1 to activate Ras and stimulate T cell proliferation. Another key proliferative pathway activated by IL-2 is phosphorylation of STAT-5 by JAK kinases. STAT-5 is recruited to IL-2 beta phosphorylated tyrosines at multiple positions, including Y338, Y392 and Y510. Once phosphorylated, STAT-5 enters the nucleus to regulate the transcription of several genes, some proliferative, such as cyclin genes, and others that are involved in T cell immune function such as cytokine genes. The suppressors of cytokine activation, SOCS-3 and SOCS-1, oppose phosphorylation and activation of STAT-5 and JAK1 caused by IL-2. PI3 kinase is another protein recruited to IL-2 receptor beta chain tyrosines when phosphorylated. Activation of PI3 Kinase also contributes to the proliferative activity of IL-2 in T cells. The role of other tyrosines in the IL-2 receptor beta chain, Y355, Y358 and Y361, is not yet clear, but may be involved in signaling by the protein kinase p56lck. In addition to stimulating T cell activation and proliferation, IL-2 activation blocks T cell apoptosis through multiple pathways. Among the genes activated by STAT-5 are BCL-xL, an inhibitor of apoptosis, and fas-ligand, an activator of apoptosis in cells expressed the fas receptor. PI3 kinase also contributes to anti-apoptotic activity of IL-2 through AKT activation. T cell responses to IL-2 must be coordinated in part in the complex protein-protein interactions with the IL-2 receptor beta chain. (BioCarta)
Myosin Phosphatase Pathway definition: The phosphorylation of myosin affects its role in smooth muscle contraction, platelet formation, and possibly other processes. Phosphorylation by myosin light chain kinase (MLCK) increases myosin activity and dephosphorylation by myosin phosphatase decreases myosin activity. CPI, a factor that binds to and inhibits myosin phosphatase, is a target of phosphorylation by PKC and PKN. The inhibitory activity of CPI is regulated by its own phosphorylation state; when CPI is phosphorylated, its inhibitory activity is increased. The activation of signal transduction cascades such as GPCR pathways can lead to activation of PKC, phosphorylation of CPI, inhibition of myosin phosphatase, increased myosin phosphorylation, and increased smooth muscle contraction or platelet release. The action of histamine in vasoconstriction, for example, may be mediated by activation of PKC through the histamine receptor, resulting in phosphorylation of CPI-17, increased inhibition of myosin phosphatase, and increased smooth muscle contraction. (BioCarta)
NFAT Pathway definition: Hypertrophy associated with both hypertension and obstruction to ventricular outflow leads to pathologic cardiac growth and it is associated with increase morbidity and mortality. Symptomatic ventricular disease takes a growing toll on the health of nations. As other cardiovascular diseases such as stroke and myocardial infraction are in decline as causes of mortality, the heart failure problem becomes increasingly urgent. Congenital heart defects occur in 1% of live births and fetal heart malformations are implicated in many pregnancies that end in still-birth or spontaneous abortion. The current paradigm suggests that the heart adapts to excess of hemodynamic loading by compensatory hypertrophy, which under condition of persistent stress, over time evolves into dysfunction and myocardial failure. There is considerable evidence that direct effects of increased mechanical stress are sensed within the ventricular wall and that signal is critical for the generation of growth responses. Despite compelling statistics we still do not understand biochemically why heart defects are so prevalent. A single transcriptional regulator initially associated with the activation of the T-cells (NFATc4) has been shown to link genetic and environmental causes of one class of congenital heart disorders, birth defects involving valve and septum formation. Within the endocardium, specific inductive events appear to activate NF-ATc: it is localized to the nucleus only in endocardial cells that are adjacent to the interface with the cardiac jelly and myocardium, which are thought to give the inductive stimulus to the valve primordia. Treatment with FK506, a specific calcineurin inhibitor, prevents nuclear localization of NF-ATc4. Activated CaMK stimulates calcineurin, which than acts through NF-ATc4 in association with GATA4, to induce hypertrophy. A model for the proposed role of calreticulin in the regulation of cardiac development requires a myogenic signal from extracellular space to activate the production of IP3 that results in the release of Ca2+ from ER under the regulation of calreticulin (CRT). Increased intracellular Ca2+ binds to calmodulin (CaM) and activates calcineurin (CaN). CaN dephosphorylates NF-ATc4 that translocates to the nucleus. In the nucleus NF-AT forms complexes with the GATA-4 and other transcription factors leading to activation of transcription of genes (e.g., ANF, a-actin, b-myosin, TNFa, ET-1, Adss1) essential for cardiac development. (BioCarta)
Prion Pathway definition: Transmissible spongiform encephalopathy (TSE) is thought to result from the structural conversion of cellular prion protein, PrP(C), into a misfolded oligomeric form, PrP(Sc). PrP is a cell membrane GPI anchored glycoprotein that is expressed in most tissues and in high levels in the nervous system. Some likely cellular functions of PrP are (1) cell protection against oxidative stress, (2) induction of neuronal cell adhesion, neurite extension and maintenance, and (3) neuroprotective signalling through a cAMP/PKA-dependent pathway. (BioCarta)
RELA Pathway definition: The rel/NF-kB family of transcription factors regulates the activity of genes involved in the immune response, hematopoiesis, and inflammation. NF-kB is a complex of two proteins, p65 (rel) and p50. NF-kB is held inactive in the cytoplasm by I-kB, until signals initiated by TNF or several other factors lead to the phosphorylation and degradation of I-kB and the subsequent release of NF-kB to bind DNA and activate genes. The activation of transcription by NF-kB requires transcriptional coactivators such as p300 and CBP to interact with the rest of the transcriptional apparatus. These coactivators posses enzyme activity, acting to catalyze the posttranslational acetylation of proteins on lysine groups. Acetylation of histones has been known for some time to occur in transcriptionally active chromatin regions. Histone deacetylase (HDAC) enzymes reverse the acetylation of histones. As with other signals, there an off-switch as well as an on-switch for NF-kB activation. The signal to terminate gene activation by NF-kB involves regulation of NF-kB acetylation. P300 and CBP recruited by NF-kB to the transcriptional complex acetylate RelA. Acetylated NF-kB proteins do not interact with I-kB and so continue stimulating transcription. To turn off NF-kB dependent transcription, the histone deacetylase HDAC3 binds to and deacetylates RelA, which then interacts strongly with I-kB once again and is inactivated. The reformed complex of NF-kB and I-kB is exported from the nucleus to the cytoplasm where it replenishes the pool of inactive NF-kB awaiting the next activation signal. The activity of other proteins may also be regulated by acetylation in a similar manner. (BioCarta)
Regulatory Pathway definition: An elaboration of the known or inferred interactions controlling the expression of a product.
AIF Pathway definition: Programmed cell death is induced by many different factors and involves numerous signaling pathways, some dependent on caspase proteases and others that are caspase independent. Like cytochrome C, AIF (apoptosis-inducing factor) is a protein found in mitochondria that is released from mitochondria by apoptotic stimuli. While cytochrome C is linked to caspase-dependent apoptotic signaling, AIF release stimulates caspase-independent apoptosis, moving into the nucleus where it binds DNA. DNA binding by AIF stimulates chromatin condensation, and DNA fragmentation, perhaps through recruitment of nucleases. DNA-binding by AIF occurs through a distinct domain of the protein in a manner that does not relay on specific DNA sequences. AIF also has another domain that acts as an NADH oxidase, a redox enzyme. The NADH oxidase activity of AIF is separable from its DNA-binding activity and is not required for AIF to induce apoptosis. In this role, AIF protects against apoptosis rather than inducing apoptosis. In mice down regulation of the AIF gene created harlequin mice with oxidative damage to neurons and increased neuronal cell death. Loss of AIF also increased sensitivity to peroxides, suggesting that AIF may act as a peroxide scavenger. The mechanism by which AIF protects against peroxide damage is not clear, but may involve a more indirect mechanism than direct peroxide scavenging since the enzyme does not appear to have this activity in vitro. Elucidating further the role of AIF as a redox enzyme will shed further light on its normal function in mitochondria as well as its role in apoptosis and disease. (BioCarta)
ALK Pathway definition: Heart formation is cued by a combination of positive and negative signals from surrounding tissues. Inhibitory signals that block heart formation in anterior paraxial mesoderm include Wnt family members expressed in dorsal neural tube and anti-BMPs expressed in the axial tissues (i.e., noggin in the notochord). Wnt signaling pathway, which is essential for setting up the entire body pattern during embryonic development, involves glycogen synthase kinase-3 (GSK3). In the absence of Wnt signaling, GSK3 is active and phosphorylates b-catenin resulting in its degradation by ubiquitin-mediated proteolysis. Activation of Wnt signaling inhibits GSK3, thereby preventing phosphorylation of b-catenin, which is then able to move to the nucleus. There it associates with members of the LEF-1/TCF family of transcription factors, which activate the transcription of genes like cyclin-D1, myc, and MMPs. The Wnt signaling pathway is blocked by a family of secreted proteins such as crescent and Dkk-1 sufficient for induction of heart formation in posterior mesoderm. BMP signaling can also be blocked by the BMP antagonists noggin and chordin, which are secreted from the notochord and cooperate with Wnts to prevent cardiogenesis. Receptors for BMPs, members of the transforming growth factor-beta (TGFb) superfamily, are persistently expressed during cardiac development, yet mice lacking type II or type IA BMP receptors die at gastrulation and cannot be used to assess potential later roles in creation of the heart. Activin receptor-like kinase 3 (ALK3) is specifically required at mid-gestation for normal development of the trabeculae, compact myocardium, interventricular septum, and endocardial cushion. Cardiac muscle lacking ALK3 is specifically deficient in expressing TGFb2, an established paracrine mediator of cushion morphogenesis. In humans, congenital heart defects occur with a prevalence of at least 1% in newborns, and are even more common in death before term. Most frequent are defects in septation and the cardiac valves, and few single gene etiologies are known. The invariable defects in myocardium and AV cushion resulting from congenital deletion of ALK3 provide strong support for its assessment as a candidate gene in human congenital heart disease. (BioCarta)
BARD1 Pathway definition: BRCA1 is a breast and ovarian cancer tumor suppressor protein that associates with BARD1 to form a RING/RING heterodimer. The BRCA1/BARD1 RING complex functions as an ubiquitin (Ub) ligase with activity substantially greater than individual BRCA1 or BARD1 subunits. The BRCA1 tumor suppressor forms a heterodimer with the BARD1 protein, and the resulting complex functions as an E3 ubiquitin ligase that catalyzes the synthesis of polyubiquitin chains. UbcH5c and UbcH7 also interact with the BRCA1/BARD1 complex with similar affinity (not shown on this figure). Although the in vivo substrate(s) is not yet known, BRCA1 has been observed to undergo autoubiquitination and is capable of monoubiquitinating histones 2A and 2AX in vitro. (Biocarta)
Calcineurin Pathway definition: The differentiation of keratinocytes constantly replenishes the upper layers of human skin we lose each day. One factor that contributes to terminal keratinocyte differentiation is increased levels of intracellular calcium. Adding calcium to the medium of cultured keratinocytes elevates intracellular calcium and triggers differentiation. Intracellular calcium levels are also increased in response to phospholipase C activation, producing IP3 and releasing calcium from stores in the ER. Intracellular calcium alters multiple signaling pathways, one of which is binding to calmodulin to activate the serine-threonine protein phosphatase calcineurin. Calcineurin dephosphorylates and activates the transcription factor NFAT and both calcineurin and NFAT are expressed in differentiating keratinocytes. Activated NFAT can regulate transcription through binding its own cognate DNA binding site. One marker of keratinocyte differentiation, the p21 gene, is activated by NFAT by a different mechanism, with NFAT activating the p21 promoter by acting as a coactivator for the transcription factors Sp1 and Sp3.Another protein activated by calcium that may be involved in keratinocyte differentiation is protein kinase C (PKC). One substrate of activated PKC is MARCKS (myristoylated alanine-rich kinase C substrate). Phosphorylation of MARCKS by PKC in intact keratinocytes is not induced during calcium-induced differentiation, but does increase when tested in vitro. PKC activity is increased by calcium during keratinocyte differentiation but PKC MARCKS phosphorylation is blocked by the formation of a complex between calmodulin and MARCKS. The immunosuppressants cyclosporin-A (CsA) and FK506 inhibit T cell activation through indirect inhibition of NFAT activation and have several side effects including changes in the skin, suggesting that calcineurin activity may play a role in normal skin physiology. CsA is used to treat psoriasis, a disease involving abnormal proliferation of skin cells. The activity of CsA in treating psoriasis may involve inhibition of immune cells, but may also directly involve inhibition of calcineurin activity in keratinocytes. (BioCarta)
Calmodulin Pathway definition: The calcium/calmodulin-dependent kinases (CaMKs) are involved in a large number of cellular responses induced by hormones, neurotransmitters and other signaling. Elevation of calcium functions as a major second messenger, where the intracellular concentration of calcium can be maintained at extremely low levels and subsequently increased following specific calcium-mobilizing stimuli. There are many buffers to the calcium fluctuations including membrane pumps and calcium-binding proteins that create discrete spatial control of its effectors and their targets. The current family of multifunctional calcium/calmodulin (CaM)-dependent protein kinases (CaMKs) consists of CaMKI, CaMKII and CaMKIV. These kinases translate and co-ordinate the calcium fluctuations into the appropriate cellular responses via phosphorylation. These kinases are partially regulated by the intracellular calcium receptor calmodulin (CaM), and have common as well as unique features in their structure, regulation and activation. CaMKII, CaMKI and CaMKIV, have an autoregulatory domain that restricts or inhibits enzymatic activity in the absence of calcium/CaM. Calcium/CaM binding alone produces maximal activity of CaMKII, whereas CaMKI and CaMKIV have an activation loop that requires phosphorylation of a threonine residue by CaMK kinase (CaMKK) for maximal activity. Two genes (alpha and beta) for CaMKK, which is also regulated by CaM, have been identified. The highest expression of these isoforms occurs in the brain but the activity of the CaMKs has been identified in most cell types. CaMKIV has a post-calmodulin autophosphorylation step that is not observed in CaMKI. The CaMKII multimer can autophosphorylate either the autoregulatory domain or the CaM-binding domain, producing diverse effects in its regulation and sensitivity to Calcium/CaM. Autophosphorylation of CaMKII can produce Calcium/CaM- independent activity (autonomous activity), without affecting its maximal Calcium/CaM-stimulated activity. The CaMKII autophosphorylation involves a kinase cascade of sorts, with each subunit of the multimeric enzyme acting as both kinase and kinase kinase. Autophosphorylation establishes a 1000-fold increase in the affinity for its activator Calcium/CaM (also known as CaM trapping); however, autophosphorylation within the CaM-binding domain following CaM dissociation of activated/autophosphorylated enzyme restricts or prevents CaM from rebinding (CaM capping). The mechanisms and consequences of autophosphorylation are central to the CaMKII enzyme's complex regulatory behavior enabling it to become differentially activated at different frequencies and levels of calcium spikes. The target proteins for the CaMKs are very similar. An example target of the CaMKs is the transcriptional activating protein CREB. The phosphorylation states of CREB after CaMK phosphorylation differ by the additional phosphorylation of CREB at serine 142 that functions as an additional inhibitory site. This difference appears to be the result of adjacent amino acids. (BioCarta)
Centrosome Pathway definition: Protein kinase A regulatory subunit RIIalpha (PKA-RIIa) is tightly bound to centrosomal structures during interphase through interaction with the A-kinase anchoring protein AKAP350 (also known as AKAP450 and CGNAP), MAP2 and Pericentrin. This diagram illustrates these three PKA-RII binding complexes. The cyclin B-p34(cdc2) kinase (CDK1) has been shown to phosphorylate PKA-RIIa on T54 and this has been proposed to alter the subcellular localization of PKA-RIIa at the on set of mitosis. It has been demonstrated that PKA-RIIa dissociates and redistributes from centrosomes at mitosis. The focal point of this illustration is the AKAP350 complex. In addition to binding PKA-RIIa, AKAP350 binds PKN (Takahashi et al 1999) and the phosphatases PP1 and PPA2 (Takahashi et al 1999). PKN is a serine/threonine protein kinase, having a catalytic domain homologous to the PKC family in the C-terminal region and a unique regulatory region in the N-terminal region. PKN is activated by a small GTPase RhoA and unsaturated fatty acids such as arachidonic acid. The binding of both kinases and phophatases by the same scaffold protein provides a focal point where physiological events, such as cell cycle progression and intracellular membrane traffic, may be regulated by phosphorylation state of specific protein substrates. There are at least 4 isoforms of AKAP350 which lead to the possibility that they may behave differently at different subcellular locations. MAP2 is a member of a group of proteins that provide microtubule stabilization. MAP2 affinity appears to be dependent on PKA phosphorylation of MAP2. Pericentrin is also an AKAP (Diviani and Scott). Pericentrin binds Dynein which is also regulated by PKA leading to the possibility that pericentrin positions PKA to regulate dynein function (Diviani and Scott). (BioCarta)
ChREBP Pathway definition: Although insulin and glucagon play important roles in regulating the response of cells to nutrients, cells also respond to carbohydrates through transcriptional regulation by the glucose responsive transcription factor ChREBP. ChREBP, carbohydrate responsive element binding protein, is a transcription factor that is activated by high levels of carbohydrates and repressed by cAMP. The activation of ChREBP by elevated carbohydrate levels increases the activity of genes involved in glucose metabolism such as pyruvate kinase, a rate-limiting enzyme in glycolysis, increasing the overall rate of utilization of carbohydrates. Excess carbohydrates also increase the transcription of genes that convert carbohydrates to triglycerides in the liver for storage in adipose tissue. cAMP regulates ChREBP activity by activating PKA, which phosphorylates ChREBP. Phosphorylation of ChREBP at ser(196) inactivates nuclear import and phosphorylation at Thr(666) prevents DNA binding by ChREBP. A metabolite of glucose activates protein phosphatase PP2A that then dephosphorylates both sites on ChREBP in response to increased glucose levels and increases ChREBP activity. Other pathways also regulate ChREBP activity and response to nutrients. High fat diets repress ChREBP activation by increasing AMP in liver cells, activating the AMP kinase. Phosphorylation of ChREBP by AMP kinase inactivates ChREBP and blocks glucose induction of ChREBP, linking dietary fatty acids to the regulation of carbohydrate metabolism. (BioCarta)
Endocytosis Pathway definition: Reliable neurotransmitter release requires the presence of sufficient numbers of synaptic vesicles. The process of synaptic vesicle endocytosis (SVE) is coordinated by a group of proteins called dephosphins. The current set of seven known dephosphins are nerve terminal proteins with little or no structural homology but satisfy two essential criteria: they are essential for SVE and they are rapidly and coordinately dephosphorylated in response to a calcium influx through voltage-dependent calcium channels. The calcium signal is mediated by calmodulin (CaM) and calcineurin. Each dephosphin plays an essential role in overlapping phases or segments of the cycle. The four phases of SVE are nucleation, invagination, fission and uncoating. The nucleation phase initiates with the activation of CaM/Calcineurin and the subsequent dephosphorylation of AP180. AP180 and clathrin are then recruited to the membrane by AP2 and PtdIns(4,5)P2. Nucleation is completed by the addition of epsin and eps15. Invagination proceeds with the formation of the amphiphysin1/2 heterodimer and its addition to the maturing vesicle surface complexes. The final components, dynamin and synaptojanin, are recruited to the budding vesicle by the amphiphysin1/2 heterodimer. Dynamin forms a complete ring around the vesicle neck and completes fission via its PtdIns(4,5)P2 stimulated GTPase activity. After internalization the vesicle is quickly uncoated, in a process believed to be mediated by synaptojanin, and is accompanied by the disassembly of clathrin. (BioCarta)
Fibrinolysis Pathway definition: Clot formation and fibrinolysis is a balance of plasmin activation/inhibition and thrombin-thrombomodulin activity that regulates fibrin polymer formation and degradation. Active thrombin is produced by the cleavage of prothrombin in the intrinsic thrombin activation pathway or the extrinsic thrombin activation pathway. Cleavage of fibrinogen by thrombin releases the fibrin monomers that auto-polymerize within seconds into fibrin threads or fibers. The coagulation cascade has many feedback loops. One example is the binding of thrombin to the fibrin polymers resulting in a reduction in soluble thrombin. The fibers form a more stable clot as a result of the covalent bonds formed by activated factor XIII enzyme (also known as Fibrin-stabilizing factor). These fibers form a mesh that traps platelets, blood cells and plasma to form a clot. The removal of the clot is caused by plasmin cleavage of the fibrin monomers into soluble fibrin degradation products. Plasmin is formed by the cleavage of plasminogen between Arg561 and Val562. Plasmin is a two-chain trypsin-like serine protease. Plasminogen activator inhibitor 1 (PAI1) and plasminogen activator inhibitor 2 (PAI2) inhibit cleavage of plasminogen by tissue-type plasminogen activator (tPA) or urokinase plasminogen activator (uPA). The presence of fibrin fibers and fibrin degradation products [(DD)E1 and (DD)E2] exert a two-fold stimulation of tPA and uPA. Plasmin activity is also inhibited by alpha2-antiplasmin. Thrombin activatable fibrinolysis inhibitor (TAFI) is a carboxy-peptidase B-like proenzyme activated by the thrombin-thrombomodulin dimer. TAFI cleaves (DD)E2 to separate DD and E fragments which do not enhance the activation of tPA or uPA and results in a reduced feedback signal. Overabundance or increased activity of the plasminogen activator inhibitors or reduced presence or function of tPA or uPA can result in atherosclerotic disease and venous thrombosis due to an increase in fibrin deposition or formation of a thrombus. Thrombosis can also result from plasminogen deficiency caused by a lack of protein or lack of functional protein. Reduced or depleted levels of alpha2-antiplamin can result in severe bleeding disorders. (BioCarta)
LDL Pathway definition: Low-density lipoprotein (LDL) is a plasma lipoprotein particle whose lipid component includes cholesterol and triglycerides and is commonly referred to as bad cholesterol due to its role promoting atherogenic heart disease. LDL in the plasma originates from very-low density lipoprotein (vLDL) produced by the liver with the apoprotein B-100. vLDL is converted to LDL by the action of lipoprotein lipase, an enzyme that hydrolyzes triglycerides in vLDL, removing them from the vLDL particle and releasing free fatty acids. The removal of triglycerides from vLDL by lipoprotein lipase leaves a greater proportion of cholesterol, increasing the density of the particle and changing it to LDL. Atherogenic heart 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. One of the first steps in the development of atherogenic heart disease is the passage of LDL out of the arterial lumen and into the arterial wall. Once there, the lipids in LDL are chemically modified and oxidized. Oxidized LDL stimulates inflammatory signaling by neighboring endothelial cells, releasing chemokines and cytokines such as M-CSF and MCP-1 and recruiting monocytes into the arterial wall. Once there, monocytes differentiate into macrophages and internalize modified LDL. These macrophages continue to internalize LDL, becoming enlarged and full of lipid. These cells accumulate in tissue and are transformed into foam cells, dying and forming part of the atherogenic plaque. Therapeutic intervention in atherogenic heart disease focuses first on lowering plasma LDL levels through diet and medication. The statins are drugs commonly used to block cholesterol production and increase the expression of the LDL receptor by the liver, removing LDL from circulation. Blocking LDL oxidation may also protect against atherogenesis, and may be the mechanism by which antioxidants such as vitamin E are proposed to reduce heart disease. Blocking the uptake of LDL by macrophages or inhibiting the inflammatory reaction against modified LDL may also offer routes to reduce the formation of atherogenic plaques. (BioCarta)
LIS1 Pathway definition: LIS1 can bind to MT bundles; however, phospho-LIS1 binding to MT bundles is mediated through the distal zinc finger motif of CLIP-170. When the distal zinc finger motif of CLIP-170 is mutated, the phospho-LIS1 isoform can no longer bind to MT bundles. This can also explain why p150/dynactin is not recruited to the MT bundles. CLIP-170 targets the dynein/dynactin complex to the MT, using phopho-LIS1 as an adapter; the motor complex, being in the proximity of the MT, associates with it. The initial static link to the MT provided by CLIP-170 is released by its hyperphosphorylation and the retrograde dynein/dynactin-dependent movement of the cargo (endocytic vesicle, kinetochore, etc.) takes place. Doublecortin (DCX) is placed close to the LIS1 pathway based on its interaction with LIS1 and its role in microtubule dynamics. (BioCarta)
Longevity Pathway definition: A demonstrated means to increase lifespan in a wide range of organisms is through the restriction of caloric intake. Reducing the consumption of calories increases the lifespan of many different organisms, including mice. Caloric restriction not only increases lifespan, but decreases age-related deterioration of systems and physiological responses, reducing age related diseases like cancer and neurodegenerative disease. Although caloric restriction has not been demonstrated experimentally to increase human lifespan, short-term changes in physiological measures like insulin responsiveness have been observed. Caloric restriction in animals reduces the levels of plasma glucose and insulin and reduces inflammatory responses and may reduce oxidative stress through reduced oxidative metabolism, further contributing to the health benefits of reduced calorie intake. The reduction in inflammation may be related to reduced plasma glucose and in humans could reduce an inflammation connection to cancer, heart disease, and Alzheimer's disease. Genetic analysis has indicated several genes that influence lifespan, particularly those that alter pituitary development, reduce growth hormone secretion, reduce food intake, and reduce apoptosis (p66 Shc). All of these appear to converge on an IGF-1 receptor pathway and to reproduce many of the effects of caloric restriction. Although dwarf mice with defective growth hormone or IGF-1 signaling also have significantly increased lifespan, humans with defects in growth hormone signaling tend to develop diseases that shorten their lifespan. One of the downstream actions of IGF-1 signaling is to repress stress resistance proteins including antioxidant enzymes like superoxide dismutase and heat shock proteins, so a reduction in IGF signaling may extend lifespan by increasing the expression of stress resistance genes. The link between caloric restriction and IGF signaling may be the increased expression of stress resistance proteins. In addition to the IGF-1R mutation, p66 Shc mutation also increases lifespan without significant aberration of other systems. Shc is a target of IGF-1R phosphorylation, and a major inducer of cellular responses to oxidative stress. Shc increases levels of intracellular reactive oxygen species, repressing the forkhead factor FKHRL1. Although FKHRL1 is also involved in apoptosis, in the absence of Shc, FKHRL1 mediates increased resistance to oxidative stress. Exploration of the genes that induce longevity in animal models may enlighten the role of these genes in human disease and lifespan. (BioCarta)
MTA3 Pathway definition: Approximately 30% of breast carcinomas lack ER expression. Presumably, these breast cancers become estrogen independent through genetic alterations that bypass the requirement for ER-dependent stimulation of cell proliferation. As such, estrogen receptor is a key regulator of proliferation and differentiation in mammary epithelia and represents a crucial prognostic indicator and therapeutic target in breast cancer. Mechanistically, estrogen receptor induces changes in gene expression through direct gene activation of a number of genes (e.g., cathepsin D, HSP27, alpha-tubulin, glyceraldehyde-3-phosphatase, Pdzk1, Greb) and also through the biological functions of target loci. The product of human MTA3 has been identified as an estrogen-dependent component of the Mi-2/NuRD transcriptional corepressor in breast epithelial cells and demonstrates that MTA3 constitutes a key component of an estrogen-dependent pathway regulating growth and differentiation. The absence of estrogen receptor or of MTA3 leads to aberrant expression of the transcriptional repressor Snail, a master regulator of epithelial to mesenchymal transitions. Aberrant Snail expression results in loss of expression of the cell adhesion molecule E-cadherin, an event associated with changes in epithelial architecture and invasive growth. MTA3 is the mechanistic link between estrogen receptor status and invasive growth of breast cancers. (BioCarta)
PPAR Pathway definition: Similar to other nuclear hormone receptors, PPAR acts as a ligand activated transcription factor. Upon binding fatty acids or hypolipidemic drugs, PPARa interacts with RXR and regulates the expression of target genes. These genes are involved in the catabolism of fatty acids. Conversely, PPARg is activated by prostaglandins, leukotrienes, and anti-diabetic thiazolidinediones and affects the expression of genes involved in the storage of the fatty acids. PPARb is only weakly activated by fatty acids, prostaglandins, and leukotrienes and has no known physiologically relevant ligand. However, data from PPARb null mice suggest PPARb does serve a role in fatty acid metabolism and perhaps in skin proliferation and cancer. (BioCarta)
Phosphoinositide Pathway definition: Nine currently identified phosphoinositide 3-kinases (PI 3-K) constitute a subfamily of lipid kinases that catalyze the addition of a phosphate molecule on the 3-position of the inositol ring of phosphoinositides. Phosphatidylinositol (PtdIns), the precursor of all phosphoinositides (PI), constitutes less than 10% of the total lipid in eukaryotic cell membranes. Approximately 5% of cellular PI is phosphorylated at the 4-position (PtdIns-4-P), and another 5% is phosphorylated at both the 4- and 5-positions (PtdIns-4, 5-P2). However, less than 0.25% of the total inositol-containing lipids are phosphorylated at the 3-position, consistent with the idea that these lipids exert specific regulatory functions inside the cell, as opposed to a structural function. Here we have chosen to highlight a group of the phosphoinositide targets of the PI3-Ks and their downstream targets. The downstream effects of these PI-3 targets are indicated, illustrating the important role the PI3Ks have in cell function and survival. (BioCarta)
Salmonella Pathway definition: Pathogenic Salmonella enter cells such as those of the intestinal epithelium by altering cellular cytoskeletal structure and inducing membrane ruffling of the infected cell. Salmonella is able to alter the cytoskeleton and membrane through the action of secreted bacterial Sip proteins, SopE, SopB, and SptP that are inserted into the cytosol of the infected cell. Sip proteins encoded by Salmonella are required for the action of SopE and for the invasion of epithelial cells. SipA stabilizes actin filaments, inducing membrane ruffling and perhaps focusing membrane changes where bacteria are localized to allow their entry. SipC produces a similar effect on actin filaments and cytoskeletal structure. SopE acts as an exchange factor on Rac1 and Cdc42, two GTPases in the Rho family that regulate actin cytoskeleton. The activation of Rac2 and Cdc42 by Salmonella SopE induces changes in cytoskeleton structure that allow bacterial entry into the cell. SopB is another salmonella protein that acts as an inositol polyphosphate phosphatase and also stimulates Cdc42 and Rac1. One of the cellular targets of both Cdc42 and Rac1 that affects actin structure is the Arp2/3 complex. Cdc42 and Rac1 activate Wasp, which activates Arp2/3. Activated Arp2/3 induces the formation of actin Y branches, which in combination with changes in actin caused by SipA and SipC help to form lamellipodia, and causes membrane ruffling, leading to entry of Salmonella into the affected cell. After the initial infection, cells quickly return to their normal morphology, a process that depends on the action of the bacterial protein SptP. While SopE acts as an exchange factor, SptP acts as a GTPase activating protein to inactivate Rac1 and Cdc42 once again. This inactivation of the original entry mechanism provides an example of the delicate balance between infectious organisms and their host. (BioCarta)
proteasomal ubiquitin-dependent protein catabolic process definition: The chemical reactions and pathways resulting in the breakdown of a protein or peptide by hydrolysis of its peptide bonds, initiated by the covalent attachment of ubiquitin, and mediated by the proteasome. [GOC:go_curators]
farnesyl diphosphate biosynthetic process, mevalonate pathway definition: The pathway that converts acetate, in the form of acetyl-CoA, to farnesyl diphosphate (FPP) through a series of mevalonate intermediates. Farnesyl diphosphate is an important substrate for other essential pathways, such as biosynthesis of sterols. [GOC:pz, MetaCyc:PWY-922]
carbon fixation by 3-hydroxypropionate cycle definition: An autotrophic carbon dioxide fixation pathway by which two molecules of carbon dioxide are fixed to form glyoxylate. Acetyl coenzyme A (acetyl-CoA) is assumed to be converted to malate, and two CO2 molecules are thereby fixed. Malyl-CoA is thought to be cleaved to acetyl-CoA, the starting molecule, and glyoxylate, the carbon fixation product. [GOC:jl, PMID:11418572, PMID:15838028]
Biochemical Pathway definition: An elaboration of the sequence of chemical reactions leading from one compound to another taking place in living tissue.
Pathway definition: A set or series of interactions, often forming a network, which biologists have found useful to group together for organizational, historic, biophysical, or other reasons.
Biosynthetic Pathways definition: Sets of enzymatic reactions occurring in organisms and that form biochemicals by making new covalent bonds.
CVT pathway definition: A constitutive biosynthetic process that occurs under nutrient-rich conditions, in which two resident vacuolar hydrolases, aminopeptidase I and alpha-mannosidase, are sequestered into vesicles; these vesicles are transported to, and then fuse with, the vacuole. This pathway is mostly observed in yeast. [PMID:12865942, PMID:15659643]
Glucuronidation definition: An inactivating and detoxification pathway for a variety of exogenous and endogenous molecules, including drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids and bile acids. Glucuronic acid is highly soluble in water and is often linked to poisonous substances to allow for subsequent elimination and to hormones to allow for easier transport. Also, drugs are commonlyconjugated to glucuronic acid to allow for easier delivery. Excretion occurs via urine or bile.
pathway definition: Chemin, route, voie.
pathway definition: Sentier.
chemin definition: Voie, route pratiquée pour communiquer, pour aller d’un lieu à un autre.
chemin definition: Zone sur laquelle on circule, et que l’on suit pour garder sa direction.
chemin definition: Toute ligne ou voie qu’on parcourt, ou qu’on peut parcourir, pour aller d’un lieu à un autre.
chemin definition: Tout parcours, tout déplacement suivi par un objet mobile.
chemin definition: Moyen, conduite, évolution suivie par quelqu’un, qui mène à quelque fin.
route definition: Voie praticable par les voitures.
route definition: Ensemble des '''routes'''.
route definition: Grande allée percée dans un bois, dans une forêt, pour la commodité du charroi, de la chasse, de la promenade, etc.
route definition: Direction qu’on suit ou qu’on peut suivre, par terre, par mer (cap) ou par les airs, pour aller en quelque lieu.
route definition: Action de cheminer, de voyager.
route definition: Parcours des astres, des eaux, etc., se dirigeant d’un point vers un autre.
route definition: Conduite qu’on tient pour arriver à quelque fin, les moyens qui y mènent.
sentier definition: Chemin étroit au travers des champs, des bois, etc.
sentier definition: #* ''Suivre les '''sentiers''' de la vertu.''