Selected differentially expressed genes in amygdala
Selected differentially expressed genes in amygdala
Positive relationships between PRKAR2A and other components at different levels (count: 1)
Genetic/epigenetic locus
Protein and other molecule
Cell and molecular pathway
Neural system
Cognition and behavior
Symptoms and signs
Environment
Positive relationship network of PRKAR2A in MK4MDD
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Note:
1. The different color of the nodes denotes the level of the nodes.
Genetic/Epigenetic Locus
Protein and Other Molecule
Cell and Molecular Pathway
Neural System
Cognition and Behavior
Symptoms and Signs
Environment
MDD
2. Besides the component related relationships from literature, gene mapped protein and protein mapped gene are also shown in the network.
If the mapped gene or protein is not from literature, square node would be used instead of Circle node.
Accordingly, the relationship is marked with dot line.
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Hover the node will show the level of the node and hover the edge will show the evidence/description of the edge.
3. The network is generated using Cytoscape Web
Negative relationships between PRKAR2A and MDD (count: 0)
Negative relationships between PRKAR2A and other components at different levels (count: 0)
Insulin binding to its receptor results in the tyrosine phos......
Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. Akt also leads to mTOR-mediated activation of protein synthesis by eIF4 and p70S6K. The translocation of GLUT4 protein is also elicited through the CAP/Cbl/TC10 pathway, once Cbl is phosphorylated by INSR. Other signal transduction proteins interact with IRS including GRB2. GRB2 is part of the cascade including SOS, RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription. SHC is another substrate of INSR. When tyrosine phosphorylated, SHC associates with GRB2 and can thus activate the RAS/MAPK pathway independently of IRS-1.More...
Apoptosis is a genetically controlled mechanisms of cell dea......
Apoptosis is a genetically controlled mechanisms of cell death involved in the regulation of tissue homeostasis. The 2 major pathways of apoptosis are the extrinsic (Fas and other TNFR superfamily members and ligands) and the intrinsic (mitochondria-associated) pathways, both of which are found in the cytoplasm. The extrinsic pathway is triggered by death receptor engagement, which initiates a signaling cascade mediated by caspase-8 activation. Caspase-8 both feeds directly into caspase-3 activation and stimulates the release of cytochrome c by the mitochondria. Caspase-3 activation leads to the degradation of cellular proteins necessary to maintain cell survival and integrity. The intrinsic pathway occurs when various apoptotic stimuli trigger the release of cytochrome c from the mitochondria (independently of caspase-8 activation). Cytochrome c interacts with Apaf-1 and caspase-9 to promote the activation of caspase-3. Recent studies point to the ER as a third subcellular compartment implicated in apoptotic execution. Alterations in Ca2+ homeostasis and accumulation of misfolded proteins in the ER cause ER stress. Prolonged ER stress can result in the activation of BAD and/or caspase-12, and execute apoptosis.More...
Repression of Pain Sensation by the Transcriptional Regulator DREAM
The molecular events that lead to the perception of pain are......
The molecular events that lead to the perception of pain are a key research field in medicine and drug discovery. The opioid receptors modulate pain signaling in response to endogenous peptide ligands and opiate drugs such as morphine. The kappa opioid receptor plays a key role in the profound analgesia of opiates and is activated by the endogenous peptide ligand dynorphin, encoded by the prodynorphin gene. Production of prodynorphin is transcriptionally regulated by a downstream regulatory element (DRE) in the prodynorphin gene. A transcription factor called DREAM (DRE antagonistic modulator) binds to the DRE and represses prodynorphin transcription when bound. DREAM binds calcium with 4 EF-hand motifs and the binding of DREAM to DNA is repressed in the presence of calcium. Many transcription factors are regulated by calcium indirectly through calcium sensitive kinases and phosphatases, but DREAM is unique to date in being a transcription factor that directly binds calcium and is regulated by calcium binding. DREAM may also regulate other genes such as c-fos. DREAM is expressed in spinal cord neurons in regions involved in pain signaling. The regulation of prodynorphin expression by DREAM also leads to the hypothesis that DREAM is involved in pain signaling. Transgenic mice lacking the DREAM gene were unusually pain insensitive and had elevated spinal levels of dynorphin and tonic activation of the kappa opioid receptor, supporting this hypothesis. Other functions of DREAM may exist such as regulation of presenilins and potassium channel activity in the heart. DREAM is also known as calsenilin and KChIP3 through its association with these other proteins. These processes were not affected in mice lacking the DREAM gene however.More...
Stathmin and breast cancer resistance to antimicrotubule agents
Stathmin is a ubiquitous, cytosolic 19-kDa protein, which is......
Stathmin is a ubiquitous, cytosolic 19-kDa protein, which is phosphorylated on up to four sites in response to many regulatory signals within cells. Its molecular characterization indicates a functional organization including an N-terminal regulatory domain that bears the phosphorylation sites, linked to a putative alpha-helical binding domain predicted to participate in coiled-coil, protein-protein interactions. In addtion to the protein kinases that phospjhorylate Stathmin such as CaMK, MAPK, p34cdc2, PKA, a few other proteins have been suggested to interact with stathmin in vivo. One of them was identified as BiP, a member of the hsp70 heat-shock protein family. Another is a previously unidentified, putative serine/threonine kinase, KIS, which might be regulated by stathmin or, more likely, be part of the kinases controlling its phosphorylation state. Finally, two proteins, CC1 and CC2, predicted to form alpha-helices participating in coiled-coil interacting structures. It has been also suggest that the action of antimicrotubule drugs can be affected by stathmin in at least two ways: (a) altered drug binding; and (b) growth arrest at the G2 to M boundary. Mutant p53 breast cancers exhibiting high levels of stathmin may be resistant to antimicrotubule agents.More...
Protein kinase A regulatory subunit RIIalpha (PKA-RIIa) is t......
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). Another example of AKAP/PKA interaction is illustrated in the AKAP95 role in mitosis and chromosome dynamics pathway.More...
Mechanism of Gene Regulation by Peroxisome Proliferators via PPARa(alpha)
The most recognized mechanism by which peroxisome proliferat......
The most recognized mechanism by which peroxisome proliferators regulated gene expresssion is through a PPAR/RXR heterodimeric complex binding to a peroxisome proliferator-response element (PPRE) (classical mechanism). However, there are the possibility of several variations on this theme: 1). The peroxisome proliferator interacts with PPAR that preexists as a DNA complex with associated corepressors proteins. The interaction with ligand causes release of the corepressor and association with a coactivator, resulting in the classical mechanism. 2). The peroxisome proliferator interacts with PPAR as a soluble member of the nucleus. The binding of ligand results in RXR heterodimerization, DNA binding and coactivator recruitment. 3). In this scenario, PPAR exists in the cytosol, perhaps complexed to heat shock protein 90 and/or other chaperones. Binding of peroxisome proliferator causes a conformational change and translocation into the nucleus. Scenarios 4 and 5 require regulation of gene expression via non-classical mechanisms: 4). PPAR is capable of interacting with, and forming DNA binding heterodimers with, several nuclear receptors including the thyroid hormone receptor. The binding site for this non-RXR heterodimer need not be the classic DR-1 motif found in the PPRE. 5). PPAR may participate in the regulation of gene expression witout binding to DNA. By association with transcription factors such as c-jun or p65, PPAR diminishes the ability of AP1 or NFB to bind to their cognate DNA sequences, respectively. Also shown in this scheme are two means to modify the peroxisome proliferator response. Most importantly, growth factor signaling has a pronounced affect on PPAR via post-translational modification. PPAR is a phosphoprotein and its activity is affected by insulin. Several kinase pathways affects PPARa's activity, although the specific kinases and phosphorylation sites have not been conclusively determined.More...
Nitric oxide (NO) has a number of important physiological ac......
Nitric oxide (NO) has a number of important physiological actions in the cardiovascular system. In the heart, NO plays role in keeping the vessels patent via vasodilation and prevention of platelet aggregation. It also plays an important role in regulating the force and rate of contraction. In vivo NO is released by shear stress of ligands that increase intracellular Ca2+ in endothelial cells. The increase intracellular Ca2+ activates nitric oxide synthase III (NOSIII) by promoting the binding of Ca/Calmodulin to the enzyme. NOSIII, which is resident in the Golgi complex, is transported together with caveolin-1 to the caveolae at the plasma membrane via vesicles. Shear stress signals via a potassium channel and the cytoskeleton, which results in tyrosine phosphorylation of specific proteins, activation of phosphatidylinositol 3-kinase, and subsequently in activation of Akt kinase. Akt activation by shear stress but also by VEGF activates NOSIII by serine phosphorylation, which increases the affinity of NOSIII for calmodulin. After agonist binding at the plasma membrane, NOSIII-activating receptors translocate to caveolae. VEGF receptor signals via its tyrosine kinase domain. Furthermore, agonist receptors activate calcium channels of the endoplasmic reticulum (ER) via phospholipase C and inositol 1,4,5-trisphosphate. This calcium flux induces binding of calmodulin to NOSIII, whereas the NOSIII-caveolin-1 interaction is disrupted. At the same time, NOSIII is translocated into the cytosol. On binding of calmodulin, NOSIII generates NO, is enhanced by the interaction with Hsp90. Once activated, NOSIII catabolizes L-arginine to NO, which diffuses out of the cell. NO stimulates guanylate (G-) cyclase and increases cGMP levels. cGMP activates cGMP-dependent protein kinase (PKG), cGMP-inhibited phosphodiesterase (PDEIII), and cGMP-stimulated phosphodiesterase (PDEII). PKG may reduce the force and rate of contraction, possibly by phosphorylating troponin I or by phosphorylating phospholamban. PDEIII is inhibited by the increases in cGMP brought about by NO. This may result in an increase in cAMP and cAMP-dependent protein kinase (PKA). PKA in turn activates Ca2+ channels, countering the effects of PKG. In contrast, cGMP may stimulate PDEII, reduce cAMP levels and PKA activity, and thereby reduce Ca2+ channel activity. Ach, acetylcholine. CAT-1, cationic amino acid transporter.More...
Proposed model for b2-AR- and prostanoid-receptor-mediated P......
Proposed model for b2-AR- and prostanoid-receptor-mediated PLC and calcium signalling. Receptors coupling to Gs stimulate AC, resulting in elevated cAMP levels and activation of Epac1. Epac1 then catalyses GTP-loading on Rap2B, which leads to PLC-e activation. The proposed pathway may involve additional signalling components to attain PLC stimulation. The action of cAMP seems to be independent of PKA; Instead, the cAMP-activated Rap-GEF Epac seems to serve as a cAMP effector, inducing GTP loading and, hence, activation of Rap2B, which then leads to specific activation of PLC-e, which has been shown to interact with Rap GTPases. It is an attractive hypothesis, therefore, that the Rap-dependent PLC and calcium signalling pathway reported here is not restricted to Gs-and AC-coupled receptors, such as the b2-AR and the prostanoid receptor, but could be used by other receptors as well.More...
Multiple antiapoptotic pathways from IGF-1R signaling lead to BAD phosphorylation
IGF-1R, the type 1 receptor for insulin-like growth factor, ......
IGF-1R, the type 1 receptor for insulin-like growth factor, mediates cell survival and growth in response to its ligands IGF-1 and IGF-2. This tyrosine kinase receptor is widely expressed in many cell types and is a key mediator of growth. Overexpression or activation of IGF-1R may be involved in the proliferation of transformed cells, making inhibition of IGF-1R signaling a strategy for the development of cancer drugs. IGF-1R activates three signaling pathways that converge to phosphorylate BAD protein and block apoptosis. The first pathway activated by IGF-1R stimulates PI3-kinase and the AKT pathway to phosphorylate BAD and block apoptosis. A second pathway activated by IGF-1R involves ras mediated activation of the map kinase pathway to block apoptosis. A third pathway involves interaction of raf with mitochondria in response to IGF-1R activation. The convergence of these pathways to block apoptosis may enhance the IGF-1R response.More...
The A-kinase anchor protein 13 (AKAP13, also known as AKAP-L......
The A-kinase anchor protein 13 (AKAP13, also known as AKAP-LBC) is one of a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. AKAP13 is a splice variant of the oncogene Lbc. Alternative splicing of the AKAP13 gene results in at least 3 transcript variants encoding different isoforms containing a Dbl oncogene homology (DH) domain and a pleckstrin homology (PH) domain. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. These splice variants contain a fragment that was originally identified as Ht31 which acts as a scaffolding protein to regulate the Rho signaling pathway and as protein kinase A-anchoring protein creating a coordination of these two signalling pathways. Diviani et al. found that in HEK293 cells LPA induced stimulation preferentially activates AKAP13 via G-alpha12. As yet targets for the anchored PKA have not been identified. AKAP13 and Rho do not appear to be phosphorylated by PKA. Diviani et al also found that the Lbc oncogene and protooncogene splice variant show higher activation and stress fiber localization. This appears to be a result of the presence of N terminal inhibitory sequences. A similar model of regulation has been proposed for Dbl and Vav.More...
NFAT and Hypertrophy of the heart (Transcription in the broken heart)
Hypertrophy associated with both hypertension and obstructio......
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 signals 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-cellsMore...
The mammalian calpain gene family currently contains 13 dist......
The mammalian calpain gene family currently contains 13 distinct large subunit products most of which complex with one of two smaller 30kDa subunits. ( An excellent introduction to the calpain family can be found on a web site created by Valery Thompson http://ag.arizona.edu/calpains/index.html ) One of the most carefully studied functions of the calpains is the regulation of integrin-mediated cell migration. Calpains digests the links between the actin cytoskeleton and several focal adhesion complex proteins; talin, paxillin and focal adhesion kinase. The release from the focal adhesion complex facilitates migration. Calpestatin is an inhibitor expressed in most cells. Calpestatin binds the four inhibitory domains of calpain. Release from calpestatin does not activate calpain. Activation requires additional signaling, coactivators and an appropriate calcium concentration. During cell migration calpain1 (mu-calpain) acts at the leading edge as a response to integrin signals or calcium fluxuations due to the stretch activated calcium channels. Calpain1 cleaves the target proteins, talin, exzrin, paxillin and the cytoplasmic tail of the integrins B1(a) and B3(b) to release the adhesion and form new adhesions. Calpain2 (M-calpain) is believed to be membrane bound and functions at the trailing edge of the migrating cell to cleave the integrins in response to growth factor receptor signals. PKA functions to down regulate or inhibit calpain2. Disease related notes: In Alzheimers disease, amyloid peptides interfere with calpain activity causing a mislocalization of cdk5. Deregulated cdk5 hyperphosphorylates tau promoting cell death in neurons. Mutations in the muscle specific calpain p94 lead to Limb Girdle muscular dystrophy 2A (LGMD2A). Over activity of calpains due to elevated calcium leads to tissue damage in the heart and brainMore...
The defects in cAMP-regulated chloride channel CTFR are beli......
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 adenulate 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.More...
GATA3 participate in activating the Th2 cytokine genes expression
CD4+ helper T cells differentiate into distinct subtypes, Th......
CD4+ helper T cells differentiate into distinct subtypes, Th1 and Th2 cells. Th2 cells are involved in the response to extracellular helminthe parasites and allergic responses and secrete a distinct set of cytokines including IL-4, IL-5 and IL-13. The development and differentiation of T cells is influenced by many factors, including transcription factors such as GATA-3, a transcription factor associated with induction of Th2 cells. Factors that increase cAMP levels in Th2 cells activate p38 kinase, which phosphorylates and activates GATA-3 independently of PKA. Cells expressing GATA-3 develop the profile of Th2 cells, secreting IL-4, IL-5 and IL-13. These cytokines are found in a gene cluster together and are regulated coordinately by GATA-3. Binding of GATA-3 in the regulatory regions of these genes alters chromatin structure, increasing accessibility to other transcription factors. Activation of the T cell receptor through interaction with antigen on antigen presenting cells activates NFAT and other transcription factors that cooperate with GATA-3 in inducing Th2 cell differentiation. Dominant negative GATA-3 can repress the secretion of these cytokines and block the airway inflammation that causes asthma. Blocking GATA-3 action such as through antisense treatment has been suggested as a therapeutic strategy to treat asthma. GATA-3 has also been implicated in developmental processes such as the development of the inner ear.More...
Activation of Csk by cAMP-dependent Protein Kinase Inhibits Signaling through the T Cell Receptor
Interaction of T cell receptor with specific antigen in the ......
Interaction of T cell receptor with specific antigen in the context of MHC II activates a signal transduction pathway that leads to T cell activation. In the T cell receptor signaling pathway, the src family kinases Lck and Fyn are activated to phosphorylate proteins in the T cell receptor complex which recruit and activate the ZAP70 kinase. The activation of ZAP70 phosphorylates downstream targets that activate MAP kinase pathways and cause T cell activation. The CD45 phosphorylase also plays a role in T cell receptor signaling, dephosphorylated Lck and Fyn to activate them. Other factors modulate T cell receptor activation. Csk (COOH-terminal Srk kinase) phosphorylates Lck and deactivates it, opposing the action of CD45. The phosphorylation of Lck by Csk inhibits T cell receptor signaling and inhibits T cell activation. Csk activity is regulated in T cells by PKA, the cAMP-dependent protein kinase activated by the second messenger cAMP. The activity of Csk also appears to depend on other factors such as CBP, which recruits Csk to the plasma membrane in lipid rafts where other signaling factors such the T cell receptor complex are localized. CBP also directly activates Csk.More...
Transcription Regulation by Methyltransferase of CARM1
Several forms of post-translational modification regulate pr......
Several forms of post-translational modification regulate protein activities. Recently, protein methylation by CARM1 (coactivator-associated arginine methyltransferase 1) has been observed to play a key role in transcriptional regulation. CARM1 associates with the p160 class of transcriptional coactivators involved in gene activation by steroid hormone family receptors. CARM1 also interacts with CBP/p300 transcriptional coactivators involved in gene activation by a large variety of transcription factors, including steroid hormone receptors and CEBP. One target of CARM1 is the core histones H3 and H4, which are also targets of the histone acetylase activity of CBP/p300 coactivators. Recruitment of CARM1 to the promoter region by binding to coactivators increases histone methylation and makes promoter regions more accessible for transcription. Another target of CARM1 methylation is a coactivator it interacts with, CBP. Methylation of CBP by CARM1 blocks CBP from acting as a coactivator for CREB and redirects the limited CBP pool in the cell to be available for steroid hormone receptors. Other forms of post-translational protein modification such as phosphorylation are reversible in nature, but as of yet a protein demethylase is not known.More...
Glutamatergic-mediated nitric oxide (NO) production occurs v......
Glutamatergic-mediated nitric oxide (NO) production occurs via the N-methyl-D-aspartic acid (NMDA) postsynaptic density protein 95 (PSD95)-neuronal nitric oxide synthase (NOS1) ternary complex. The increased intracellular Ca2+ stimulates the interaction of nNOS and calmodulin (CaM) and the translocaton of nNOS from the plasma membrane to the cytoplasm. The dephosphorylation of nNOS by Calcineurin catalyzes the conversion of arginine to citrulline and nitric oxide (NO), which turns on guanylate cyclase and the various cGMP regulated signaling pathways.More...
The G-protein coupled receptor (GPCR) family transduces extr......
The G-protein coupled receptor (GPCR) family transduces extracellular signals across the plasma membrane, activating cellular responses through a variety of second messenger cascades. These receptors provide rapid responses to a variety of stimuli, and are often rapidly attenuated in their signaling. Failure to attenuate GPCR signaling can have dramatic consequences. One method to attenuate GPCR signaling is by removal of the stimulus from the extracellular fluid. At the synapse, removal of neurotransmitter or peptide signaling molecules is accomplished by either reuptake or degradation. Acetylcholine is removed from synapses through degradation by the enzyme acetylcholinesterase. Inhibition of acetylcholinesterase results in prolonged signaling at the neuromuscular junction, and uncontrollable spasms in humans caused by nerve gas or in insects by some insecticides. Inhibition of acetylcholinesterase is also used therapeutically to treat Alzheimer's disease, compensating for the loss of cholinergic neurons. Transporters for serotonin, dopamine, GABA and noradrenaline remove these neurotransmitters from the synapse to terminate signaling. Antidepressants such as Prozac inhibit reuptake of serotonin and many drugs of abuse such as cocaine act by blocking reuptake of dopamine or adrenaline. Reuptake not only terminates signaling, but can also conserve neurotransmitter through recycling back into the presynaptic cell. The next step in the attenuation of GPCR signaling is receptor desensitization, in which receptors are modified to no longer transduce a signal even if the stimulus is still present. Desensitization of GPCRs occurs through protein kinases that phosphorylate the GPCR to turn off signaling. Downstream protein kinases such as PKA and PKC turned on by GPCR signaling can phosphorylate the activated GPCR and other GPCRs to prevent further signaling. G-protein receptor kinases (GRKs) are a family of kinases that specifically phosphorylate only agonist-occupied GPCRs. GRKs attenuate GPCR signaling in concert with arrestins, proteins that bind GRK-phosphorylated GPCRs to disrupt interaction with G-protein and to terminate signaling. Reducing the number of receptor expressed on the cell surface can also attenuate receptor signaling. Many GPCRs are removed from the cell surface by receptor-mediated endocytosis when they are activated. Endocytosis of activated GPCRs appears to be stimulated by GRKs and arrestins. Once internalized, receptors can either be degraded in lysosomes or they can be recycled back to the cell surface.More...
Progesterone (Pg) binds to both intracellular iPR and plasma......
Progesterone (Pg) binds to both intracellular iPR and plasma membrane- bound mPR. (Right Top) After binding to Pg, iPR is recruited to the membrane associated protein tyrosine kinase p60c- src, which induces activation of the MAPK signaling pathway. This results in activation of p90Rsk and the subsequent phosphorylation and inactivation of Myt1, which favors formation of the activated cell cycle complex cyclin B-Cdc2. Activation of cyclin B-Cdc2 causes breakdown of the germinal vesicle and the initiation of oocyte maturation. (Left). In contrast, binding of Pg to mPR leads to inhibition of adenylyl cyclase (AC) through activation of Gi or inhibition of Gs. This leads to a decrease in the cAMPdependent kinase PKA, which relieves inhibition of Cdc25C (the phosphatase that dephosphorylates and activates cyclin B-Cdc2) and also indirectly promotes the activation of MAPK signaling. PKA also regulates the initiation of oocyte maturation through other effects that are independent of PKA activity.More...
G-aS-coupled receptors stimulate adenylyl cyclase (AC), whic......
G-aS-coupled receptors stimulate adenylyl cyclase (AC), which synthesizes cAMP from ATP. In contrast Gai-coupled receptors inhibit AC and so reduce cAMP formation. The bg subunits from Gai and other G proteins are able to activate the MAP kinase pathways and PLCb. GPCRs coupled to the Gaq family of G proteins stimulate PLCb, which cleaves membrane phospholipids to produce IP3, which mobilizes intracellular calcium, and DAG, which activates PKC. Second messenger pathways then activate a range of effector systems to change cell behaviour; in many cases this includes the regulation of gene transcription. Dotted line shows a more indirect pathway.More...
Sonic Hedgehog (Shh) is one of a family of three secreted pr......
Sonic Hedgehog (Shh) is one of a family of three secreted proteins, including Indian Hedgehog (Ihh) and Desert Hedgehog (Dhh), that play distinct and crucial roles in development. The morphogenic signal Shh provides in the developing CNS induces proliferation of neuronal precursor cells in the developing cerebellum and other tissues. Proliferative signaling by Shh is involved in the development of cancer, including specific brain and skin cancers such as basal cell carcinomas, while activation of Shh signaling in neurons may also provide a means to induce neuronal regeneration. Mitogenic Shh signaling does not appear to involve Map kinase pathways, but may involve induction of Cyclin D1 expression to maintain Rb in the hyperphosphorylated state and allow progression through the G1 phase of the cell cycle. Activation of myc may be one mechanism by which Shh induces cell cycle progression. Activation of Shh proliferative signaling occurs through binding to a receptor complex including Patched (Ptc-1) and Smoothened, a G-protein coupled receptor. Patched is an integral membrane protein with twelve transmembrane domains that acts as an inhibitor of Smoothened activation. Patched has been classified as a tumor suppressor due to its inhibition of Smoothened and the presence of inactivated Ptc-1 mutations in some cancers. One possibility is that Ptc-1, which resembles transmembrane channels, may not directly associate with Smoothened but may repress Smoothened signaling by transporting an endogenous Smoothened inhibitor across the plasma membrane into the cytoplasm. Small non-peptidic agonists and antagonists of the Shh pathway have been identified and appear to act at the level of the Smoothened receptor, providing pharmacological tools to study Shh signaling. The pathway downstream of the Smoothened receptor has remained somewhat unclear, but involves the Gli family of transcriptional activators, including Gli-1, Gli-2, and Gli-3, homologs of the drosophila gene cubitis interruptis. Kinases including GSK-3 and PKA oppose activation of the Shh pathway, perhaps by regulating the stability of Shh pathway intermediate signaling factors transcription factors. Supressor of Fused (SUFU) interacts directly with Gli proteins, repressing Shh signaling while Dyrk1 is a kinase that acts by a distinct pathway to stimulate Gli1 activation of transcription. The multiplicity of factors involved in Shh signaling creates many opportunities for therapeutic intervention in the treatment of cancer and possibly neurodegenerative diseases.More...
Liver is the major site for carbohydrate metabolism (glycoly......
Liver is the major site for carbohydrate metabolism (glycolysis and glycogen synthesis) and triglyceride synthesis (lipogenesis). While insulin was long thought to be the major regulator of hepatic gene expression, emerging evidence show that nutrients, in particular, glucose and fatty acids, are also able to regulate hepatic genes. This diagram illustrates how glucose metabolite, rather than glucose itself, contributes to the coordinated regulation of carbohydrate and lipid homeostasis in liver through phosphorylation-dependent regulation of ChREBP (carbohydrate responsive element binding protein). ChREBP is a basic helix-loop helix/leucine zipper (bHLH/LZ) transcription factor, shuttling between the cytoplasm and nucleus in a glucose-responsive manner in hepatocytes. When serum glucose is elevated, glucose transporter (GLUT2) and glucokinase (GCK) allow for rapid uptake and equilibration of intracellular glucose levels. This flux of glucose promotes, via the hexose monophosphate shunt pathway (HMP Shunt), the formation of xylulose-5-phosphate (Xu-5-P), which activates protein phosphatase 2A (PP2A) to dephosphorylate ChREBP (Ser196) and promote its nuclear localization. PP2A further dephosphorylates ChREBP in the nucleus, allowing it to dimerize with the bHLH/LZ transcription factor Max-like protein X (MLX) and activate transcription of a number of glycolytic and lipogenic genes containing a ChoRE, such as liver-type pyruvate kinase (L-PK), acetyl-CoA carboxylase 1 (ACACA), and fatty acid synthase (FASN). Upon starvation or high-fat feeding, intrahepatic levels of cAMP and AMP are elevated to activate protein kinase A (PKA) and AMP-dependent protein kinase (AMPK), respectively. PKA-mediated phosphorylation of Thr666 and Ser626 inhibits the DNA binding capacity of ChREBP; so does AMPK-mediated modification of Ser568. PKA-dependent phosphorylation of Ser196 promotes interaction with 14-3-3 and thus sequesters ChREBP in the cytosol. In summary, the phosphorylated form of ChREBP is rendered inactive due to its diminished DNA binding capacity and subcellular compartmentalization. Glucose metabolism triggers dephosphorylation of ChREBP, allowing it to enter the nucleus and activate the transcription of both glycolytic and lipogenic gene expression in liver. The fact that ChREBP/ mice are intolerant to glucose and insulin resistant suggests that ChREBP may also play a role in the pathogenesis of type 2 diabetes.More...
The function of the pro-apoptotic molecule BAD is regulated ......
The function of the pro-apoptotic molecule BAD is regulated by phosphorylation of three sites (ser 112,136 and 155). Phosphorylation at these sites results in loss of the ability of BAD to heterodimerize with the survival proteins BCL-XL or BCL-2. Phosphorylated BAD binds to 14-3-3 and is sequestered in the cytoplasm. While ser-136 phosphorylation is concordant with the activation of Akt, Ser-112 phosphorylation requires activation of the Ras-MAPK pathway. BAD Ser 155 was found to be a major site of phosphorylation induced following stimulation by growth factors and prevented by protein kinase A inhibitors.More...
Neuropeptides VIP and PACAP inhibit the apoptosis of activated T cells
Vasoactive intestinal peptide (VIP) and the structurally rel......
Vasoactive intestinal peptide (VIP) and the structurally related pituitary adenylate cyclase-activating polypeptide (PACAP), two neuropeptides present in the lymphoid microenvironment, elicit a broad spectrum of biological functions, including the modulation of innate and adaptive immunity. Another important immunoregulatory function of VIP and PACAP is their inhibition effect on AICD in T cells. They inhibit the TCR-stimulated FasL expression and apoptosis of T cell through specific receptors and induction of intracellular cAMP. VIP down-regulate c-Myc synthesis, the NF-AT-dependent Egr2 and Egr3 expression, the NF-AT and NF-kB.More...
The chromatin packaging of the genome is dynamic, changing w......
The chromatin packaging of the genome is dynamic, changing with the cell cycle and with transcriptional regulation. During mitosis, chromatin is condensed for segregation of chromosomes, while for transcription chromatin is more open. The nuclear matrix, or scaffold, is a protein network in the nucleus providing structure and regulating chromatin condensation. Regulated interactions of matrix proteins with each other, DNA and other factors in different phases of the cell cycle alter the structure and function of chromatin. AKAP95 (A-kinase anchoring protein) is a nuclear matrix associated protein that also binds DNA and different proteins during different phases of the cell cycle. The interaction of AKAP95 with DNA and proteins alters the condensation and transcription of chromatin. A specific domain of AKAP95 regulates its interaction with the nuclear matrix and another regulates its association with DNA. One key protein that AKAP95 interacts with is the cAMP-dependent protein kinase, PKA. AKAP95 binds to PKA through a PKA RII regulatory subunit, an interaction that requires PKA phosphorylation by Cdk1. PKA activity and cAMP are reduced during entry into mitosis, but PKA recruited by AKAP95 to condensed chromosomes is essential to maintain the condensed state. Another protein recruited by AKAP95 is Eg7, a 150 kD protein recruited during mitotic chromatin condensation. Eg7 is a part of a multiprotein condensin complex, recruiting another key component of mitotic chromatin condensation. Modification of the core histones through phosphorylation regulates chromatin condensation. Histone H3 interacts with the condensin complex, and is phosphorylated during mitosis. Histone H3 phosphorylation by Aurora-2 induces chromatin condensation, and dephosphorylation by PP1 promotes chromatin decondensation for reentry into interphase. AKAP95 may play a role during the regulation of chromatin structure for transcription during interphase as well. The interaction of AKAP95 with the p68 RNA helicase recruits this enzyme to the nuclear matrix during interphase. Other nuclear RNA helicases interact with transcription factors and cofactors, suggesting that the p68 RNA helicase also may regulate interactions of transcription complexes.More...
Transcription factor CREB and its extracellular signals
The transcription factor CREB binds the cyclic AMP response ......
The transcription factor CREB binds the cyclic AMP response element (CRE) and activates transcription in response to a variety of extracellular signals including neurotransmitters, hormones, membrane depolarization, and growth and neurotrophic factors. Protein kinase A and the calmodulin-dependent protein kinases CaMKII stimulate CREB phosphorylation at Ser133, a key regulatory site controlling transcriptional activity. Growth and neurotrophic factors also stimulate CREB phosphorylation at Ser133. Phosphorylation occurs at Ser133 via p44/42 MAP Kinase and p90RSK and also via p38 MAP Kinase and MSK1. CREB exhibit deficiencies in spatial learning tasks, while flies overexpressing or lacking CREB show enhanced or diminished learning, respectively.More...
Regulation of ck1/cdk5 by type 1 glutamate receptors
Cdk5 is a cyclin dependent protein kinase involved in dopami......
Cdk5 is a cyclin dependent protein kinase involved in dopaminergic signaling in the neostriatal region of the brain. The role of cdk5 in dopamine responses occurs through phosphorylation of DARPP-32. Caseine kinase 1 (CK1) also regulates DARPP-32 phosphorylation and dopamine signaling. The phosphorylation of DARPP-32 by cdk5 reduced dopamine signaling. Depending on its phosphorylation state, DARPP-32 inhibits either protein phosphatase 1 (PP1) or PKA. The role of mGLUR1 in this process is supported by the induction of cdk5 and CK1 activity by the mGLUR1 agonist DHPG and the subsequent phosphorylation of DARPP-32 associated with DHPG treatment of nigrostriatal neurons. CK-1 and Ckd5 inhibitors block the DHPG induced DARPP-32 phosphorylation. Dopamine exerts a positive signal that increases dopamine response by reversing phosphorylation of DARPP-32 at threonine-75. Dopamine initiates this pathway through activation of the D1 dopamine receptor, a Gs coupled GPCR, elevating cAMP and activating PKA. PKA activates protein phosphatase 2A (PP2A) which dephosphorylates DARPP-32 and increases dopamine responsiveness. This also removes the inhibition of PKA by DARPP-32, forming a positive feedback loop for further DARPP-32 inactivation by PKA. Activation of the D2 dopamine receptor has the opposite effect, shifting the DARPP-32 population toward the threonine-75 phosphorylated form.More...
A number of inactive tetrameric PKA holoenzymes are produced......
A number of inactive tetrameric PKA holoenzymes are produced by the combination of homo- or heterodimers of the different regulatory subunits associated with two catalytic subunits. When cAMP binds to two specific binding sites on the regulatory subunits, these undergo a conformational change that causes the dissociation of a dimer of regulatory subunits bound to four cAMP from two monomeric, catalytically active PKA subunits.More...
Pancreatic beta cells integrate signals from several metabol......
Pancreatic beta cells integrate signals from several metabolites and hormones to control the secretion of insulin. In general, glucose triggers insulin secretion while other factors can amplify or inhibit the amount of insulin secreted in response to glucose. Factors which increase insulin secretion include the incretin hormones Glucose-dependent insulinotropic polypeptide (GIP and glucagon-like peptide-1 (GLP-1), acetylcholine, and fatty acids. Factors which inhibit insulin secretion include adrenaline and noradrenaline.More...
Opioids are chemical substances similar to opiates, the acti......
Opioids are chemical substances similar to opiates, the active substances found in opium (morphine, codeine etc.). Opioid action is mediated by the receptors for endogenous opioids; peptides such as the enkephalins, the endorphins or the dynorphins. Opioids possess powerful analgesic and sedative effects, and are widely used as pain-killers. Their main side-effect is the rapid establishment of a strong addiction. Opioids receptors are G-protein coupled receptors (GPCR). There are four classes of receptors: mu (MOR), kappa (KOR) and delta (DOR), and the nociceptin receptor (NOP).More...
Glucagon-like Peptide-1 (GLP-1) is secreted by L-cells in th......
Glucagon-like Peptide-1 (GLP-1) is secreted by L-cells in the intestine in response to glucose and fatty acids. GLP-1 circulates to the beta cells of the pancreas where it binds a G-protein coupled receptor, GLP-1R, on the plasma membrane. The binding activates the heterotrimeric G-protein G(s), causing the alpha subunit of G(s) to exchange GDP for GTP and dissociate from the beta and gamma subunits. The activated G(s) alpha subunit interacts with Adenylyl Cyclase VIII (Adenylate Cyclase VIII, AC VIII) and activates AC VIII to produce cyclic AMP (cAMP). cAMP then has two effects: 1) cAMP activates Protein Kinase A (PKA), and 2) cAMP activates Epac1 and Epac2, two guanyl nucleotide exchange factors. Binding of cAMP to PKA causes the catalytic subunits of PKA to dissociate from the regulatory subunits and become an active kinase. PKA is known to enhance insulin secretion by closing ATP-sensitive potassium channels, closing voltage-gated potassium channels, releasing calcium from the endoplasmic reticulum, and affecting insulin secretory granules. The exact mechanisms for PKA's action are not fully known. After prolonged increases in cAMP, PKA translocates to the nucleus where it regulates the PDX-1 and CREB transcription factors, activating transcription of the insulin gene. cAMP produced by AC VIII also activates Epac1 and Epac2, which catalyze the exchange of GTP for GDP on G-proteins, notably Rap1A.. Rap1A regulates insulin secretory granules and is believed to activate the Raf/MEK/ERK mitogenic pathway leading to proliferation of beta cells. The Epac proteins also interact with RYR calcium channels on the endoplasmic reticulum, the SUR1 subunits of ATP-sensitive potassium channels, and the Piccolo:Rim2 calcium sensor at the plasma membrane.More...
Neurotrophins (NGF, BDNF, NT-3, NT-4/5) play pivotal roles i......
Neurotrophins (NGF, BDNF, NT-3, NT-4/5) play pivotal roles in survival, differentiation, and plasticity of neurons in the peripheral and central nervous system. They are produced, and secreted in minute amounts, by a variety of tissues. They signal through two types of receptors: TRK tyrosine kinase receptors (TRKA, TRKB, TRKC), which specifically interact with the different neurotrophins, and p75NTR, which interacts with all neurotrophins. TRK receptors are reported in a variety of tissues in addition to neurons. p75NTRs are also widespread. Neurotrophins and their receptors are synthesized as several different splice variants, which differ in terms of their biological activities. The nerve growth factor (NGF) was the first growth factor to be identified and has served as a model for studying the mechanisms of action of neurotrophins and growth factors. The mechanisms by which NGF generates diverse cellular responses have been studied extensively in the rat pheochromocytoma cell line PC12. When exposed to NGF, PC12 cells exit the cell cycle and differentiate into sympathetic neuron-like cells. Current data show that signalling by the other neurotrophins is similar to NGF signalling.More...
Calmodulin (CaM) is a small acidic protein that contains fou......
Calmodulin (CaM) is a small acidic protein that contains four EF-hand motifs, each of which can bind a calcium ion, therefore it can bind up to four calcium ions. The protein has two approximately symmetrical domains, separated by a flexible hinge region. Calmodulin is the prototypical example of the EF-hand family of Ca2+-sensing proteins. Changes in intracellular Ca2+ concentration regulate calmodulin in three distinct ways. First, by directing its subcellular distribution. Second, by promoting association with different target proteins. Third, by directing a variety of conformational states in calmodulin that result in target-specific activation. Calmodulin binds and activates several effector protein (e.g. the CaM-dependent adenylyl cyclases, phosphodiesterases, protein kinases and the protein phosphatase calcineurin).More...
Glucagon and insulin are peptide hormones released from the ......
Glucagon and insulin are peptide hormones released from the pancreas into the blood, that normally act in complementary fashion to stabilize blood glucose concentration. When blood glucose levels rise, insulin release stimulates glucose uptake from the blood, glucose breakdown.More...
Many hormones that affect individual physiological processes......
Many hormones that affect individual physiological processes including the regulation of appetite, absorption, transport, and oxidation of foodstuffs influence energy metabolism pathways. While insulin mediates the storage of excess nutrients, glucagon is involved in the mobilization of energy resources in response to low blood glucose levels, principally by stimulating hepatic glucose output. Small doses of glucagon are sufficient to induce significant glucose elevations. These hormone-driven regulatory pathways enable the body to sense and respond to changed amounts of nutrients in the blood and demands for energy. Glucagon and Insulin act through various metabolites and enzymes that target specific steps in metabolic pathways for sugar and fatty acids. The processes responsible for the long-term control of fat synthesis and short term control of glycolysis by key metabolic products and enzymes are annotated in this module as six specific pathways: Pathway 1. Glucagon signalling in metabolic pathways: In response to low blood glucose, pancreatic alpha-cells release glucagon. The binding of glucagon to its receptor results in increased cAMP synthesis, and Protein Kinase A - Copyright National Academy of Sciences, U.S.A.).More...
Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARP......
Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32), was identified as a major target for dopamine and protein kinase A (PKA) in striatum. Recent advances now indicate that regulation DARPP-32 phosphorylation provides a mechanism for integrating information arriving at dopaminoceptive neurons, in multiple brain regions, via a variety of neurotransmitters, neuromodulators, neuropeptides, and steroid hormones. Activation of PKA or PKG stimulates DARPP-32 phosphorylation at Thr34, converting DARPP-32 into a potent inhibitor of protein phosphatase-1 (PP-1). DARPP-32 is also phosphorylated at Thr75 by Cdk5, converting DARPP-32 into an inhibitor of PKA. Thus, DARPP-32 has the unique property of being a dual-function protein, acting either as an inhibitor of PP-1 or of PKA.More...
The phospholipase C (PLC) family of enzymes is both diverse ......
The phospholipase C (PLC) family of enzymes is both diverse and complex. The isoforms beta, gamma and delta (each have subtypes) make up the members of this family. PLC hydrolyzes phosphatidylinositol bisphosphate (PIP2) into two second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes intracellular calcium stores while DAG activates protein kinase C isoforms which are involved in regulatory functions.More...
The activation of phosphlipase C-gamma (PLC-gamma) and subse......
The activation of phosphlipase C-gamma (PLC-gamma) and subsequent mobilization of calcium from intracellular stores are essential for neurotrophin secretion. PLC-gamma is activated through the phosphorylation by TrkA receptor kinase and this form hydrolyses PIP2 to generate inositol tris-phosphate (IP3) and diacylglycerol (DAG). IP3 promotes the release of Ca2+ from internal stores and this results in activation of enzymes such as protein kinase C and Ca2+ calmodulin-regulated protein kinases.More...
Trk receptors signal from the plasma membrane and from intra......
Trk receptors signal from the plasma membrane and from intracellular membranes, particularly from early endosomes. Signalling from the plasma membrane is fast but transient; signalling from endosomes is slower but long lasting. Signalling from the plasma membrane is annotated here. TRK signalling leads to proliferation in some cell types and neuronal differentiation in others. Proliferation is the likely outcome of short term signalling, as observed following stimulation of EGFR (EGF receptor). Long term signalling via TRK receptors, instead, was clearly shown to be required for neuronal differentiation in response to neurotrophins.More...
PRKAR2A related interactors from protein-protein interaction data in HPRD (count: 32)
Basic Information
Positive relationships between PRKAR2A and other components at different levels (count: 1)
