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Pathway Central

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Cancer related Pathways

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

Akt Signaling [ Details | Top ]
Akt (v-Akt Murine Thymoma Viral Oncogene)/ PKB (Protein Kinase-B) is a Serine/threonine Kinase that is involved in mediating various biological responses, such as inhibition of Apoptosis and stimulation of cell proliferation. Three mammalian isoforms are currently known: Akt1/PKB- Alpha, Akt2/PKB-Beta and Akt3/PKB-Gamma. All three isoforms of Akt share a common structure of three domains. The N-terminus of the protein is a PH (Pleckstrin Homology) domain, which interacts with membrane lipid products such as PIP2 (Phosphatidylinositol-3,4-Bisphosphate) and PIP3 (Phosphatidylinositol-3,4,5-Triphosphate)....

All-trans-retinoic acid signaling [ Details | Top ]
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 - New [ Details | Top ]
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)....

BRCA1 Pathway - New [ Details | Top ]
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...

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

Cellular Apoptosis Pathway [ Details | Top ]
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)...

Cyclins and Cell Cycle Regulation [ Details | Top ]
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 [ Details | Top ]
The immune system recognizes the presence of pathogens by several proteins that bind to molecules secreted by the pathogen or carried on their surface. The cells responsible for these immune responses include the B-Cells, T-Cells, macrophages, neutrophils, basophils, eosinophils, endothelial cells, or mast cells (Ref.1). These cells have distinct roles in the immune system, and communicate with other immune cells by cytokines, which control proliferation, differentiation and function of cells of the immune system. Furthermore, they are involved in processes of inflammation and in the neuronal, haematopoietic and embryonal development of an organism....

DNA Repair Mechanisms [ Details | Top ]
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 [ Details | Top ]
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...

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

Estrogen Pathway [ Details | Top ]
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...

Fas Signaling [ Details | Top ]
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....

Hedgehog - New [ Details | Top ]
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 - New [ Details | Top ]
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 [ Details | Top ]
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...

IGF1R Signaling [ Details | Top ]
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...

Integrin Signaling Pathway [ Details | Top ]
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 [ Details | Top ]
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...

JAK/STAT Pathway [ Details | Top ]
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 [ Details | Top ]
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...

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

Mitochondrial Apoptosis - New [ Details | Top ]
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 [ Details | Top ]
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...

Notch Signaling [ Details | Top ]
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...

p53 Signaling [ Details | Top ]
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...

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

PPAR Pathway [ Details | Top ]
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 [ Details | Top ]
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....

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

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

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

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

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