Topic 6 Cell Signaling

cell signaling
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Signaling molecules hormones- testosteronesite of origin: testis some actions: induces and maintains secondary male sexual characteristics **endocrine in natureSignaling molecules hormones- thyroid hormone (thyroxine)site of origin: thyroid gland some actions: stimulates metabolism in many cell types **endocrine in natureSignaling molecules local mediator- epidermal growth factor (EGF)site of origin: various cells some actions: stimulate epidermal and Manu other cell types to proliferate **paracrine in natureSignaling molecules local mediator- platelet-derived growth factor (PDGF)site origin: various cells including blood platelets some actions: stimulate cell types to proliferate **paracrine in natureSignaling molecules local mediator- Nerve growth factor (NGF)site origins: innervated cell tissues actions: promote survival of certain classes of neurons; promotes their survival and growth of their axons **paracrine in natureSignaling molecules neurotransmitters- acetylcholinesite of origins: nerve terminals some actions: excitatory neurotransmitter at many nerve-muscle synapses and in central nervous systemSignaling molecules contact-dependent signal molecules- integrinsattaches cell to the basement membrane and can initiate signaling in the cellDifferent cells respond differently to the same signalExample of acetylcholine... - acetylcholine binding to a heart pacemaker cell results in decreased rate of firing - acetylcholine binding to salivary gland cell results in secretion - acetylcholine binding skeletal muscle cell results in contraction of the cellBalance of signals received determines cell's behaviorsignals that are given to the cell result in varying the cells behaviorsApopcytosisprogrammed cell death. cellular suicide programextracellular signal molecule binds to the cell-surface receptor protein... two pathways resultGenomic pathway: internal signaling molecule enter the nucleus and results in transcription, translation, and then alter gene expression. this process is slow and could take minutes or up to hours Nongenomic pathway: does not enter the nucleus stays in they cytoplasm but also results in altered cell behavior. This process is fast seconds or minutes.Genomic Signaling PathwayExample cortisol... cortisol is a hydrophobic molecule which is it is able to enter and diffuse through the plasma membrane and has an intracellular receptor protein that it binds to. Now the cortisol and the cortisol receptor move into the nucleus and act as an initiator of transcription as they bind to the promoter region and activate the target gene.General schematic of a non-genomic signaling pathwayExtracellular signal molecule (ligand) binds to the receptor which is typically integral membrane protein. Once binding occurs an internal signaling molecule and intracellular signaling of proteins occurs in a cascade also known as signal transduction. This continues till the intracellular signaling proteins converge onto a target protein and and an outcome is resulted cellular behavior (look at picture)Functions of signaling cascades1. Primary transduction: signaling molecule fires as long it is bound to the receptor protein (all it needs is at least the binding of one) 2. Relay: signal is relayed or in greater control or greater regulation in the pathway that has more firing. 3. Tranduce and amplify: this occurs when the pathways bifurcate (one signal binds to the receptor and several small messenger molecules carry the signal forward) so the signal is amplified. 4. Integrate: extracellular signaling molecules can integrate into one junction signal molecule 5. Distribute or Diversificate: occurs when the molecule bifurcates as the signal diversificates.bifurcatethe divine of outcomes from the same signaling pathwaycell surface receptorsHas a hydrophilic signal molecule which cannot enter the cell membrane so it benefits by having a cell-surface receptorsIntracellular receptorshas a small hydrophobic signaling molecule which can enter the cell membrane and then goes into the nucleus and leads to transcription. Examples of this include estrogen and cortisolCell surface receptor- ion channel coupled receptorsresponsible for the transport of ions and they open only when bound to a signal molecule and gives rise to signalingCell surface receptor- G protein coupled receptorsG-protein is any protein that is bound to GTP meaning it is active, when hydrolyzed to GDP it is inactive. In this process the activated G protein binds to the signal molecule and carries the signal forward to form a signaling cascadeCell surface receptor- enzyme coupled receptorsreceptors have an inherent enzyme built into them... typically a kinase. signal binds to receptor and kinase is activated initiating the cascade and carrying the signal forwardinternal signaling moleculesactivated by two means... -signaling by protein phosphorylation. No phosphate protein is turned off. If there is a phosphate the protein in the on position and is functioning. - signaling by gap binding proteins. if the G protein is bonded to the gap it is off and inactive. In order to be activated the guanine exchange factor exchanges the gdp for a gtp and activates the protein carrying out the cascade and signaling. The turning off of the protein is done via gap hydrolysis. a hydrolysis enzyme gtpase hydrolyzes the protein and turns of the proteinGuanine Exchange Factor (GEF)initiates the exchange of GDP for GTP in the nucleusAdrenaline major responses- increase in heart rate and force of contraction - glycogen breakdown - fat breakdown - cortisol secretionAdrenaline signal receptoradergenic receptor... - 7 transmembrane domains - extracellular ligand binding domain - cytoplasmic domainInactive G proteintrimeric... alpha, beta, and gamma. Alpha and gamma are linked to plasma membrane by means of lipid linked tails.G-protein coupled receptor pathwayreceptor is activated by ligand or adrenaline. When adrenaline binds to the receptor the receptor is activated and the conformation changes. the adrenaline binds to the alpha part of the trimeric adergenic receptor. This causes the gap to dissociate and a gtp attaches to the alpha subunit activating the alpha subunit and the G protein is activated as well. Now the alpha subunit of the G protein disscicates from the beta and gamma subunit of the G protein. Both of them initiate internal signaling cascade.activated alpha subunit of G proteinThis alpha subunits interacts with the enzyme adenylylcyclase. This enzyme converts atp to cAMP. cAMP is the second messenger moleculeConversion of ATP to cAMPATP made up of three phosphates. The cAMP removes 2 ATPs and forms cAMP.adenylyl cyclaseConverts ATP to cyclic AMP in response to an extracellular signal.cyclic AMP (cAMP)A compound formed from ATP that acts as a second messenger.cyclic AMP phosphodiesteraseEnzyme which catalyzes the hydrolysis of cAMP to 5'-AMPDivergence of Pathway... non-genomicSignaling pathway of adrenaline from the g-protein coupling receptorsCascade chain of the signaling pathway. Know how many signaling pathways have been activated from one signaling molecule at the endCell responses by cAMP-inactivation of glycogen synthase -activation of glucose 6-phophorylaseDivergence of pathway genomiccoverts inactivate PKA into activated PKA which can enter the nucleus this triggers kern which allows for transcriptionCell responses mediated by phospholipase C activation- glycogen breakdown -secretion of amylase (digestive enzyme) -contraction -aggregationPhospholipase CG-protein linked receptor signals phospholipase C splits PI into IP3 and DAG: 1. *IP3* increases intracellular Ca2+ 2. *DAG* activates kinases (PKC) to activate enzymesepidermal growth factor (EGF)When EGF binds to EGFR the EGF dimerizes and becomes one unit. This dimerization causes activation of the kinases which causes autophosphorylation.Autophosphorylation allows the kinase to phosphorylates tyrosine amino acids in the kinase and causes the receptor to be active. The active receptor can now bind to other adapter proteins (GRP2). The adapter protein can bind to a guanine exchange factor (Ras-GEF) which links SOS to (GEF). SOS removes the GDP off of RAS and adds GTP to RAS and therefore activating RAS. RAS proteins them activates other molecules.EGF receptor (EGFR)has a extracellular ligand binding domain, a transmembrane domain, and a cytoplasmic domain. The cytoplasmic domain has an intrinsic kinase within receptor. In the absence of EGF the kinase is inactive. the kinase is known as receptor tyrosine kinase or RTKs.Activated RAS protein-activates MAP kinase kinase kinase (RAF... sir, thr kinase) -activated MAP kinase kinase -activated MAP kinase... this can enter the nucleus and cause changes in gene expression and in nongenomic pathway it causes changes in the proteinsMitogen-activated protein kinase (MAPK)Any of a class of enzymes involved in signal transduction pathways that often activate cell division. In a cell, different types of MAPKs are organized in a series, where one activates another via phosphorylation.PI 3-kinasewhen bound to the right EGFR it is activated and active PI 3-kinase coverts inositol biphophate to inositol triphosphate. This activates protein kinase 1 which activates AKT which is a cell survival protein.Signaling Pathway Overviewsignaling cascade order- signaling molecule binds to the cell with the mutant protein x... no signal due to mutant preventing cascade to go through - signaling molecule binds to the cell with the mutant protein x with the introduction of RAS (upstream)... signaling is restored -signaling molecule binds to the cell with the mutant protein y... no signal due to mutant preventing cascade to go through -signaling molecule binds to the cell with the mutant protein y with the introduction of RAS (downstream)... no signalingdeduced order of proteins in signaling pathwaysignal binds to the receptor and receptor activates meaning it is upstream of RAS which activates x which activates y. therefore an outcome or cellular behavior is resulted.