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MEKK-MKK-p38 =
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apoptosis
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Forms of signaling
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endocrine-bloodstream paracrince-signaling cell-target cell neuronal-synapse contact dependent-emebrane bound signal membrane
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GAP ________ g proteins
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inactivates
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the alpha subunit is a
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GTPase
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the g-alpha t stimluates
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cGMP phosphodiesteras
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ERK phosphorylates ______, a transcription factor which activates serum response.
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Elk-1
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f-MLP
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is a chemoattractnt released by bactera
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Signal IN
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means that extracelluar signal molecules binds to its receptor embeeded in the plasma membrane and intiates signaling inside the cell
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Where is cAMP synthesized?
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active adenylyl cyclase
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the g-alphai/o subfamily
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inhibits adenylyl cyclase
stimluates GERK potassium channels
inhibits N and P/Q Ca2+ channels
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This cytokine receptor dimerizes and phosphorylates STATs.
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JAKs
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PKA mediated phosphorylation is reversed by
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Protein phosphotases
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Do most cell signaling molecules activate one or multiple receptor types?
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multiple
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Kinase
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an enzyme that add/cleaves phosphates to proteins
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Cyclic AMP(cAMP)
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the binding of epinephrine tothe plasma membrane of a liver cell elevates the cytosolic concentration of a compound called cyclic adenosine monophosphate or this
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Inositol triphosphate
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the pathways leading to calcium release involve still other second messengers, this is one and is produced by cleavage of a certain kind of phospholipid in the plasma membrane
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Protein phosphatases
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enzymes that can rapidly remove phosphate groups from proteins, a process called dephosphorylation
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Protein phosporylation/depho is widely used in the intracelluar signaling pathway Only three amino acids can be phosphorylated by kinase-
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Tyr Ser Thr
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What removes the phosphate which is added by kinases?
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phosphatases
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This is a cAMP dependent protein kinase that is activated by the binding of cAMP.
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PKA
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What is the cytoplasmic Ca binding protein in neurons
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Calbindin
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Once GTP is hydrolyzed, the G-alpha subunit regains its affinity for _____.
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beta-gamma
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All nicotinic receptors have ____ Ach binding sites.
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2
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Another way to regulate GPCR signaling is at the receptor level. This includes uncoupling of the receptor (______), removal of the receptor (______), or decreased synthesis of the receptor (______).
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desensitization
internalization
downregualtion
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GPCR Signaling #3
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3) Ligand expression decreases hydrolysis of GTP to GDP occurs. (Inactive G-protein w/ GDP reassociates with GPCR) As long as ligand or toxin present, G-protein will be re-activated
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what is epinephrine?
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aka adrenaline, is a catecholamine that binds to beta-andrenergic receptors located on most tissues; this binding is mediated by a rise in intracellular cAMP resulting from the activation of adenylate cyclase
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extracelluar signal molecules fall into two classes
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intracelluar receptors cell-surface receptors
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Explain the pathway for RTK
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phosphotyrosines recruit adaptor protein Grb-2Ras GEF activates G protein Ras by GDP-GTP exchangeActive Ras initiates signaling until GTP is hydrolyzed
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What is \"specificity?\"
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molecular interaction of signal and receptor
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PI is phosphorylated by _______________
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PI-kinases to yield PIP2
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Many receptors use _________
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adaptor proteins for signal transduction
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cAMP activates...
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cAMP dependent kinases such as protein kinase A and PKA
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This second messenger is the lowest in abundance of the phosphorylated derivities of PI, but the most important in signalin
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PIP2
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All forms of adenylyl cylclase are found in the _______ and are stimlated by _______.
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CNS
G-alpha S
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This type of receptor has NO CATALYTIC ACTIVITY on its own, but instead bind and instigate a conformational change in a heterotrimeric G protein.
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GPCRs
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This group of adenylyl cyclase is inhibited by PKA phosphorylation
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group III
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Nuclear targets of ERK often stimulate ________ ________.
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cellular proliferation
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GPCR & 1-TMR
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These are not mutually exclusive, Tyrosine Kinase can activate G-proteine
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G Protein-coupled receptors
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a plasma membrane receptor that works withthe help of a G protein, a protein that bindsthe energy-rich molecule GTP. Many different singaling molecules,including yeast mating factors, epinephrine and many other homrones, and neurotransmitters, use G protein-coupled receptors.
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what is involved in receptor down regulation
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lysosome, receptor, molecule
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what can make a signal molecule have different effects?
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receptor expression
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what does continuous activation of the G-prot receptor signaling require?
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continuous presence of ligand
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can binding of a protein on one cell trigger differentiation on another cell?
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yes
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ALL GPCRs
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have smiliar structures -is made of a singla polypeptide chain that crosses the plasma membrane seven times. These receptors belong to a superfamily of seven -pass transmembrane receptor proteins
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Explain vibrio cholera
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enters enterocytes alters G protein at alpha subunitGTP cannot be hydrolyzed and adenylyl cyclase remains active. High cAMP levels->phophorylation/activation of CFTR.Cl- ions move into the intestinal lumen and water follows-- diarrhea/dehydration
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Enzyme coupled receptors...
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-have a cytosolic domain which either has intrinsic enzymatic activity or activates an associated enzyme-signal binding is REQUIRED for enzymatic activity
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Another name for PP 2 B is ________. It is actviated by calcium.
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calcineurin
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One of the main cellular survival signals is mediated by the Ser/Thr kinase _________.
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Akt (aka PKB)
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Local and long-distance cell communication in animals
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animal cells can communicate via direct contact between membrane-bound cell-surface molecules, which occurs during a process called CELL-CELL RECOGNITION which is important in such processes as embryonic development and the immune response
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what does active adenylate cyclase do?
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takes ATP and generates cAMP
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how do receptors WITHOUT intrinsic exzymatic activity work?
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directly associated with cytosolic tyrosine kinase; ligand binding causes receptor monomers to dimerize; the dimerized complex interacts with and acticates one or more sytosolic tyrosine kinase
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NO gas bind and activates the enzyme
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guanyly cyclase catalyzed trasnformation of GTP to cGMP
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signaling initated inside the cell
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signal molecules can diffuse across the plasma membrane where they activiate enzymes or bind to intracelluar receptors
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What is the largest family of signal receptors?
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G-protein coupled receptors
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Describe the G protein coupled receptor signaling pathway
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Ligand binds to receptor extracellularly which activates the g protein which uses GTP to move to an effector molecule like a kinase or other enzyme
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Classes of cell surface receptors
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1- ion coupled receptors2- enzyme coupled receptor3- G-protein coupled receptor
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the solulble guanlyl cyclases include receptor for what?
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small gases- NO and CO
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these groups of GPCR has large N-termini that are involved in ligand binding
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group II and III
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This has to be released from mito in mammals before caspase 9 can be activated.
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cytochrome c
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Janus Kinase (Jak)-Signal Transducers and Activators of Transcription (STAT) Pathway #2
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2) STATs recruited to cytokine receptor
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Signal transduction pathway
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the process by which a signal on a cell's surface is converted to a specific cellular response in a series of steps
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how do receptors WITH intrinsic activity work?
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ligand binding leads to dimerization of the receptor; these receptors have iether residues of serine/threonine kinases or tyrosine kinase activity; autophosphorylation of these residues create binding sites for several cytosolic enzymes and bring them bear their membrane-bound substrates; in most cases these enzymes generate second messengers-Receptors with intrinsic tyrosine kinase activity are capable of autophosphorylation as well as phosphorylation of other substrates.
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what are the 6 signals of communication by extracellular signals?
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synthesis of signalrelease of signaltransport of signaldetection of signalchange in metabloism or gene expressionremoval of signal for response termination
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target protein for G-Proetin sub units are
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ion channels membrane bound enzymes
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How does Viagra® work?
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It uses nitrix oxide to relax smooth muscles of blood vessels. It lowers Ca which leads to relaxation
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What does calmodulin do?
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it mediates many of the effects of calcium signaling**calmodulin with bound calcium binds to and regulates many enzymes (kinases and phosphatases)
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Explain the steps of GPCR pathway
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Ligand induces receptor to form binding site for G proteinActive site binds alpha subunitalpha undergoes change and replaces GDP with GTP (alpha active and beta gamma dissociates)alpha activates adenylyl cyclase which synthesized many cAMP molecules
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An example of this family of receptors is CD45 found on T and B lymphocytes.
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Receptor Tyrosine Phosphatase (RTP)
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what does binding of a ligand to rWiea's do?
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stimulates the receptor's protein kinase activity which stimulates a signal transduction cascade leading to changes in cellular phys and/or patterns of gene expression; have a wide range of activity (prolif/differentation/survival/metab)
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What general effects do signals have on cell function?
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Opening of membrane channels Changes in enzyme activity Differences in gene transcription
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What happens once Ras-GTP activates the kinase cascade?
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Activated MAP kinase is imported into the nucleusphosphorylates serum response factor (SRF) and ternary complex factor (TCF)active SRF and TCF bind to serum response elements (SRE) in promotor regions of target genesinitiates gene expression
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what does prolonged exposure of a cell to high concentration of a ligand usually result in?
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reduction in the number of its functional receptor, thereby desenditizing the cell to the ligand; the # of receptors not reduced but activity is modified
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Regulating of protein activity by GTP binding protein
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they are in the active conformatoin with GTP bound. The protein itself hydrolyzes GTP to GDP and returns into an inative form
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Describe PLC's role in the cell
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cleaves PIP2 into DAG and IP3 which opens Ca2+ channels in rerCa and DAG activate Protein Kinase C (PKC)PKC phosphorylates many substrates that regulate metabolism and gene expression
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How do we reverse the action of PI3K?
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PTEN
dephosphorylates PI3K at the 3 position
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are the number and activity of functional receptors on the surface of cells constant?
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no, can be up or down regulated allowing the cells to respond optimally to small changes in ligand level
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Describe the life cycle of a second messenger
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They are short lived and rapidly degraded
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