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This 24 page Class Notes was uploaded by Kristin Scott on Friday April 22, 2016. The Class Notes belongs to 401 at Washington State University taught by Dr. Kim, Dr. Sheldon, Dr. Hunzicker in Spring 2016. Since its upload, it has received 8 views.
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Date Created: 04/22/16
Cell Communication All functions in the body are based on communications between cells (signals within cells) Cell communication and signaling pathways: Tells cells when to divide, to enter the cell cycle; Tells cells when to die, to undergo apoptosis; and Tells cells how to specify with development. Aberrant cell communication can lead to diseases, including cancer. Necessary for multicellular organisms Unlike unicellular organisms, multicellular organisms require elaborate cell communication mechanisms Depends on production of molecules by one cell that provides instructions to one or more target cells General Principles of Ce Communication Cell signaling begins with production of an extracellular signal molecule that alters the function of the target cell Types of Signaling: Contact dependent signaling: signal stays bound to cell that releases the signaling Paracrine signaling: signal acts locally on nearby cells o Autocrine signaling: The signal is secreted into extracellular space, then acts on the same cell that secret it. Synaptic signaling: electrical stimulus from neuron to target cell through axon and neurotransmitter Endocrine signaling: hormone secreted from endocrine cell that travels through and out of the blood stream to the target cell Autocrine signaling (a subset of paracrine signaling) Endocrine signaling: Speed: relatively slow because it relies on diffusion of signal and blood flow Precision: It has a low effective concentration of 10 M Synaptic signaling: Speed: relatively fast. o Electrical impulses of 100 meters/sec. o It travels less than 100nm. Takes less than a millisecond to diffuse across the synapse 4 Precision: effective concentration is higher. 10 M Affects only post synaptic target cells Gap junctions allow neighboring cells to share intracellular signals If one cell is unable to recognize a signal, the neighboring cell may be able to share intracellular signals through a gap junction Receptors General characteristics Extracellular signal molecules bind to receptors. Receptors are proteins. Extracellular signals usually act at low concentrations = < 10 M (< 10 nM) 8 Receptors bind signals with high affinity (Kd < 10 M) law of mass action, rate association/rate Location: plasma membrane or cytosol Extracellular signals bind to and activate specific receptors Receptors also bind antagonists that do not activate receptors (agonist activate receptors) Receptors are specific for each signal molecule Interaction of receptors with signal molecules is reversible (law of mass action) There are a finite number of receptors in a cell for each signal that a cell responds to Speed of signals binding and unbinding to receptors is important. Each target cell receives hundreds of signals and is programmed to respond in a distinct manner to each signal. If a cell does not receive any signals, it dies Specific cell response depends on the receptors present and internal machinery by which the cell integrates the signal e.g. Acetylcholine binds to same receptor but elicits distinct responses in heart muscle vs. salivary gland cells Specific cell response can also depend on the concentration of the signal (morphogen) that reaches the cell Different concentrations of the same signal will cause different cell types to emerge Speed of target cell response to an extracellular signal depends on whether signal alters activity of an existing protein or promotes gene expression. Fast: allosteric change or post translational modification (in cytosol) Slow: transcriptional changes (because the signal has to travel to the nucleus) Rapid changes in the activity of proteins, elicited by extracellular signals, are often driven by phosphorylation (fast) Because a phosphate group carries 2 charges, addition or removal of PO 4(Pi) can cause a large conformational change in a protein, changing its activity, cell location, and/or binding to other proteins (usually changes a proteins binding behavior) Phosphorylation can either increase or decrease the activity of a protein. Phosphorylation is a covalent modification catalyzed by a protein kinase and reversed by a protein phosphatase (dephosphorylation) o Protein kinases catalyze phosphorylation of three amino acids; threonine, serine, and tyrosine o PTyr & PSer/Thr have dual specificity Protein kinases & phosphatasesImportant concepts Cells contain hundreds of protein kinases and many phosphatases that are organized into complex networks of signaling pathways that help coordinate cell activity The activity of protein kinases and phosphatases is (rapidly) regulated by extracellular signals Activity of proteins is dynamic because of the combined activities of kinases and phosphatases and resulting rapid turnover of phosphate groups on a protein. Speed of target cell response also depends on turnover (rate of destruction) of intracellular molecules (RNA or protein) (regulated by extracellular signal) To reach a steady state concentration (stable amount) after turning transcription on or off, it takes at least 3 halflives (halflife X 3) Example: This molecule has a half-life of 5 minutes, so it would take 15 minutes to reach a steady state concentration after turning transcription on or of Short summary: Speed of target cell response depends on: speed of extracellular signal to reach target cell whether intracellular response is mediated by allosteric/posttranscriptional events (in cytosol) or by altered gene expression (in nucleus) o For altered gene expression, 3 halflives are required for new steady state. Cells contain an array of receptors: localized to plasma membrane localized intracellularly (in cytosol or in nucleus) Nuclear Receptors Nuclear receptors bind extracellular signals that are small hydrophobic molecules that can readily cross the plasma membrane Signals include: testosterone, progesterone, estrogen, mineral corticoids, cortisol, thyroid hormone, retinoids, & vitamin D, etc Nuclear receptors are all transcription factors Upon binding of signal (ligand) and activation of receptor, the receptor binds to DNA as a dimer and regulates transcription of one or more genes Nuclear receptor is a dimer Characteristics: specific, high affinity, reversible, activity is to be a transcription factors, protein receptors, limited number of receptors This receptor family also includes proteins that bind as unidentified ligands and are thus referred to as orphan nuclear receptors DNAbinding domains on nuclear receptors are conserved Common nuclear receptor features: DNA binding domain (DBD) is called C domains and are highly conserved o Zink finger Ligand binding domain (LBD) is called E domain and is highly conserved o signature domain AF domains o AF1: A/B is a variable domain o AF2: domain may not be present Sequence similarity of nuclear receptors: DNA binding domain is most conserved Ligand binding domain is conserved among isoforms The length of A/B domain varies. A/B domain is unique to each receptor. Some receptors lack F domain. Binding of ligand causes dissociation of inhibitory proteins & binding of co-activators Active nuclear receptors function as transcription factors to activate or repress target genes. Agonists vs. antagonists; selective receptor modulators (tamoxifen = mixed Estrogen agonist/antagonist, SRM) There is an early primary response and a delayed secondary response to hormones as ligands for nuclear receptors Early Primary Response to steroid hormone: Takes 30 minutes to 6 hours Cycloheximide inhibits translation in early response Delayed secondary response to steroid hormone: Effect of Cycloheximide (protein synthesis inhibitor) on mRNA induction Genomic response Unique to nuclear receptor family? Protein 1 is repressor for primary response gene. Protein 2 turns on secondary response. Cycloheximide therefore inhibits early primary response protein 2. 1 2 Genomic responses can take hours to days. Certain steroid hormones (eg. estrogen, progesterone, etc) can elicit a nongenomic response (MAP kinase, cAMP, PKC, Ca channel, etc.) via a membraneassociated receptor or a membrane receptor. Cell Surface Receptors Introduction: Types: ligandgated channels, Gprotein coupled receptors, enzymelinked receptors Triggers/causes: Scaffolds, signaling cascades, and switches Ligandgated channels (Ionchannel coupled receptors) Extracellular signal (often a neurotransmitter) binds to ion channel protein & opens the channel allowing entry or exit of specific ions Note that signal/ligand binding domain is always located on the outer surface of plasma membrane GProtein Coupled Receptors Gprotein spans membrane 7 times It activates enzyme Signal molecule is first messenger; activated Gprotein is second signal Activity is to activate Gprotein Enzyme Coupled Receptors Type 1: receptor activity is to be an enzyme when active (receptor becomes an enzyme) Type 2: activates an enzyme General characteristics of signaling by plasma membrane receptors: Sbring signaling proteins together, to increase efficiency, precision, and speed Signaling proteins act as molecular switches Intracellular signaling cascades: (involves protein kinases) Signals are relayed by sequential phosphorylation of kinases or proteins that regulate kinase activity Cells organize groups of intracellular signaling proteins into signaling complexes. This organization is often accomplished by scaffold proteins Preassembled complex is a type of scaffold protein. oThe whole complex can be pulled down, meaning proteins are activated in a downward direction Advantage of formation of signaling complexes: scaffold guides the interactions between successive components and enhances precision and speed of response Complex assembles after activation. The signals can’t pull down complex until it’s assembled. Receptor is scaffold in this case Phosphatase would dephosphorylate the receptor and inactivates it. Example #3 Assembly of signaling complexes depend on the presence of conserved binding domains present in many intracellular signaling proteins Domains include: PH: Pleckstrin homology domain PTB: Phosphotyrosine binding SH2: Src homology 2 domain SH3: Src homology 3 domain PY: PhophoTyr interaction PH: Pleckstrin homology domain PTB: Phosphotyrosine binding SH2: Src homology 2 domain SH3: Src homology 3 domain PY: PhophoTyr interaction PPP: proline rich motif Assembly of this signaling complex follows receptor activation. Each complex is activated, promoting the binding of the next protein 1) Phosphorylated SH2 domain of signaling protein 1 binds to tyrosine on receptor. o PH domain binds phosphorylated inositol. o Binding activates kinase activity of signaling protein 1. 2) Signaling protein 2 gets phosphorylated and then binds to PTB domain of signaling protein 1 3) Adaptor protein binds to protein 2. o The phosphorylated SH2 domain binds a tyrosine of signaling protein 2 4) PPP of signaling protein 3 binds to SH3 domain of adaptor protein o Signaling protein 2 phosphorylates signaling protein 3 Protein 1 is recruited though high affinity binding. Binding activates kinase activity, phosphorylating protein 2, activating kinase activity of protein 2. SH2 binds phosphorylated domain of protein 2 This is not a scaffold. More like a cascade. Assembly if signaling complex on phosphoinositide docking sites Activation of receptor occurs, and then the phosphoinositide will bind signaling proteins and add another phosphate (making 3 phosphates) PH domains bind Phosphoinositides There are three classes of molecular switches: 1) GTPbinding proteins (GProteins) 2) Protein kinase and phosphatases 3) Phosphoryl activation switch GTPbinding proteins (Gproteins): Binding of GTP switches protein from inactive to active state. Gproteins contain intrinsic GTPase activity, hydrolyzing GTP to GDP, switching off activity. Protein Kinase and phosphatases: Protein kinases are often organized into phosphorylation cascades, where one protein kinase phosphorylates the next protein kinase and so on in a sequence, relaying and amplifying the signal onward. Protein that is phosphorylated will turn on (usually; depends on sight of phosphorylation and proteins involved) Phosphoryl activation switch: Binding of a protein to a specific phosphorylated residue (usually Tyr) can be sufficient to activate catalytic activity of a protein, relaying the signal Signaling through Gprotein coupled receptors Mediate responses to: neurotransmitters, sense of light, smell, taste, receptors to prostaglandins and glycoprotein hormones, Important in drug development Basics: Gprotein: guanine nucleotide binding proteins αβγ = Gprotein GTP binds to α subunit, leading to the dissociation from β and γ subunits = active α is a GTPase (More complex version of Gprotein activation) 1) Signal binds receptor 2) Gprotein binds receptor 3) α subunit binds GTP causing the alpha subunit to dissociate from the β and γ subunits and also from the receptor All complexes are activated α 4) subunit binds a target protein, activating the target protein, and triggering the next event in the cascade. 5) Hydrolysis of the GTP to GDP on the α subunit causes the target protein to dissociate from the α subunit and become inactive 6) The Gprotein subunits reassociate GTPase activity of Gα subunit (to reassociate with β γ subunits) is accelerated by RGS Inactivation is regulated by Regulators of Gprotein Signaling (RGSs) or Gprotein associated proteins (GAPs) There are 19 types of Gα subunits, 4 types Gβ, and 6 types Gγ subunits We will discuss: oGαs oGαq oGαI, GβγI oGolf Gαs: 2+ Activates adenylyl cyclase & activates Ca channels Gprotein coupled receptors are coupled to stimulatory Gprotein (GαS) signals by stimulating production of cAMP ocAMP is responsible for facilitating many hormone induced cell responses Caffeine and Theophylline inhibit Phosphodiesterase, so cAMP isn’t converted to 5’AMP o Results in elevated levels of cAMP cAMP exerts most of its effects in cells by activating cAMPdependent protein kinase (PKA) o (yes, this is the actual acronym for cAMPdependent protein kinase) o 5’AMP does not activate PKA o Activated PKA catalytic subunit moves into nucleus to phosphorylate transcription factor CREB on a Ser Active PKA also phosphorylates lots of other proteins, including ion channel proteins, and metabolic enzymes. PKA is anchored to specific locations in cells via a family of Akinase anchoring proteins (AKAPs) so cAMP activating PKA is not random o Preassembled protein complex = scaffold Also targeted to AKAP is substrate and proteins that cause cAMP degradation Protein phosphorylation is very dynamic. The change in activity of a protein mediated by phosphorylation is relatively transient (fast and temporary) o Phosphatases: catalyzes dephosphorylation o Three general groups of phosphatases: 1. Serine/Threonine phosphatase 2. Tyrosine phosphatase 3. Ser/Thr/Tyr phosphatase (dual specificity) Ser/Thr Phosphatases: o Type 1: dephosphorylates many PKA substrates o Type 2A, 2B, 2C ( has two catalytic subunits) o Generally, they are composed of a single catalytic (C) subunit and one or two very diverse regulatory subunits (forming a dimer or trimer). o Regulatory subunits target phosphatase to different cellular compartments. o Type 2 has two catalytic subunits that are homologous usually. There is no homology in regulatory subunits. Regulatory subunits regulate the activity of catalytic subunit PKA is anchored to specific locations in cell via a family of Akinase anchoring proteins (AKAPs). 1. The catalytic subunit will phosphorylate the subunits that are close to it. 2. The “other protein” may be a kinase, and will phosphorylate the 4th subunit, phosphatase, 3. Phosphatase dephosphorylates the other subunits. Gαq: Gproteincoupled receptors coupled to a Gαq subunit signals by activating phospholipase Cβ PIP 2activates phospholipase Cβ and causes PIP to di2sociate into diacylglycerol and IP 3 IP 3causes Ca to be released from ER, then the Ca binds to diacylglycerol which activates protein kinase C Protein kinase C phosphorylates transcription factors, metabolic enzymes, and other proteins PI + ATP PIP + ATP PIP 2 2+ 2+ IP3 opens Ca ion channel. Second messengers: cAMP, IP , a3d Ca Protein kinase C is a Ser/Thr protein kinase, activated by diacylglycerol, calcium, and membrane phospholipid. Ca functions as a ubiquitous second messenger triggering muscle contraction, secretion, and regulates intracellular signal pathways Regulation of Calcium Ca can function as a second messenger. Its concentrations in cytosol are normally kept low. When signals open Ca 2+ channels, Ca rushes into cytosol, increasing concentration 1020 fold. Calcium pump at plasma membrane pumps calcium out of cell (against concentration gradient) uses energy from ATP hydrolysis. 2+ Ca pumps in plasma membrane, ER, and mitochondria keep calcium levels low in cytosol Plasma membrane: Uses ATP to pump Ca out of cell 2+ ER: uses ATP to pump calcium into ER and keep Ca levels in cytosol low Mitochondria: Uses an electrochemical gradient from oxidative phosphorylation to keep Ca levels low in cytosol Three types of Ca channels mediate (extracellular signalstimulated) elevation of intracellular Ca2+ 1. IP 3gated channels in ER in response to extracellular signal 2. Voltagedependent channel in plasma membrane that opens in response to membrane depolarization 3. Ryanodine receptors in ER that are activated with a rise in intracellular Ca (Ca induced Ca release) IP3 Voltage Ca binding proteins serve as transducers of cytosolic Ca signal 2+ Ca binding protein calmodulin is found in all eukaryotic cells Binding of Ca is allosteric and cooperative. Calmodulin is not an enzyme, rather it binds to other proteins and alters their activity Calmodulin targets: Plasma membrane Ca pump, ryanodine receptor (ER), calmodulindependent protein kinases, and others. 2+ Calmodulin detects spike of Ca facilitates it being pumped back out Channels in endoplasmic reticulum that transport Ca (ATP 2+ dependent Ca pumps, Ryanodine receptor, IP re3eptor) Activation of Calmodulin Kinase II IP3 is produced and causes Ca 2+ to be pumped out of ER and into cytoplasm. Calmodulin then facilities pumping Ca 2+ back into ER with Ryanodine Receptor and ATP-dependent Ca 2+ pumps Shown is one of 12 subunits. CaM Kinase II is inactive in absence of calmodulin, as a result of the interaction of between an inhibitory domain and catalytic domain. Binding of Calcium/CaM alters the conformation of the protein, allowing the C domain to phosphorylate the inhibitory domain (of neighboring subunits in complex) as well as other proteins in the cell. Autophosphorylation of enzyme complex prolongs the activity of enzyme: it traps Ca/CaM so that it doesn’t dissociate until calcium in cytosol returns to basal levels, and it converts enzyme to a calcium-independent form so it remains active when CaM dissociates. This continues till a phosphatase inactivates. GProteins Continued… GαI, GβγI inhibits adenylyl cyclase and activates K channels heart slows down as a result of an inhibitory effect of acetylcholine (open K channels makes it harder to depolarize heart cell) α subunit inhibits adenylyl cyclase while βγ subunit activates K ion channel Gαolf activates adenylyl cyclase in olfactory neurons Smell and vision depend on Gproteinlinked receptors that regulate cyclicnucleotidegated ion channels Humans can distinguish 10,000 distinct smells via olfactory neurons. Different smells are recognized by specific G proteincoupled olfactory receptors on surface of tongue cilia. Signaling by Gprotein coupled receptors: Unique characteristic of signaling from membrane receptors as compared to nuclear receptors Amplification (level of second messenger) Rapid response requires rapid return to basal levels, mediated by: o phosphodiesterases o phosphatases o Ca pumps Inactivation of GProtein Coupled Receptors Ligand dissociates off receptor Receptor “uncouples” from Gprotein= desensitization Receptor internalized Desensitiza tion Enzymelinked Cell Surface Receptors Cytosolic domain of these receptors has either an intrinsic enzyme activity or associates directly with an enzyme. Receptors generally span membrane a single time. o receptor tyrosine kinases o tyrosinekinase associated receptors o receptorlike tyrosine phosphatases o receptor serine/threonine kinases o receptor guanylyl cyclases Pathways that require regulated proteolysis: o Notch pathway o βCatenin o Sonic Hedgehog Receptor Tyrosine Kinase Receptor activation: o Dimerization (required for autoP) o transautophosphorylation Functions of phosphorylated tyrosines on receptor tyrosine kinase: 1. Phosphorylation within kinase domain alters conformation increasing kinase activity 2. Phosphotyrosines create highaffinity docking sites for binding of signaling proteins Transient association of signaling complex Insulin and IGF1 receptors bind IRS, an intermediate adaptor protein (IRS=insulin receptor substrate): activated receptor first autophosphorylates, then binds a docking protein = IRS1; Activated receptor then phosphorylates IRS1, creating docking sites for signaling molecules. Phosphorylated tyrosines serve as docking sites for proteins with SH2 domains SH2 domain: highly conserved phosphotyrosine binding domains Signaling proteins Phospholipase Cβ (PLCγ), and IP Kina3e Receptor tyrosine kinases activate PI 3inase Regulatory subunit of PI 3inase binds phosphorylated receptor via its SH2 domains PI3 kinase promotes phosphorylation of PIP , g2nerating PIP . 3 PIP 3binds to and activates proteins via their PH (pleckstrin homology) domains PIP 3activates proteins PKB/Akt for cell growth, survival, division, etc Pdk1 and Akt are anchored to PIP 3 PI3kinase generates PIP which3activates PKB/Akt for cell growth, survival, division, etc Receptor tyrosine kinases also activate the MAPK cascade: Activated by: Growth factors, GPCRs, UV irradiation, heat shock, inflammatory cytokines, interleukins, osmotic stress 1. Signal binds receptor tyrosine kinase 2. Grb2 adaptor binds to phosphorylated tyrosines via its SH2 domain and to SOS via its SH3 domain 3. Grb2 brings SOS to Ras (Ras is a small Gprotein) 4. SOS activate Ras by phosphorylating the GDP to GTP and a downstream Ser/Thr phosphorylation cascade is triggered. The major signaling pathway activated by Ras is mitogenactivated protein kinase (MAPK) pathway 5. Ras activates MAPkinasekinasekinase (RAF) MAPkinasekinase (MEK) MAPkinase (ERK) activity 6. Ras becomes inactive; GTP is hydrolyzed back to GDP (activation is transient) Summary of Gprotein coupled receptors and Receptor Tyrosine Kinase Genomic versus nongenomic actions of “nuclear” receptor family Mostly, receptors are genomic Signaling responses detected within seconds to minutes (Fast if nongenomic) Isolated cell membranes; impermeable steroidprotein conjugates Pathways regulated: PI3 Kinase, ERK/MAPK, cAMP, Ca (MAPK can lead to genomic action, others are not genomic) Mediated by classical receptors or an alternative receptor Tyrosine Kinaseassociated Receptors Cytokine Receptor family is associated with Jak (Janus kinase) Extracellular signaling molecules include the cytokines (interferons, interleukins, erythropoietin, and select hormones like growth hormone, prolactin) 1. Binding of cytokine causes receptors to dimerize and associated Jaks are brought together 2. Jaks crossphosphorylate each other on tyrosines 3. Activated Jak phosphorylates receptor again, creating docking sites for STATs and a few other proteins 4. Two STATs dock to specific phosphotyrosine on receptor via SH2 domain and Jaks phosphorylates each STAT (STAT: signal transducer and activators of transcription; latent transcription factor) 5. STATs dissociate from Jaks and dimerize and migrate to the nucleus and act as a transcription factor Cytokine receptor/Jak/Stat family of proteins regulate: Immune response to viral infection (interferons) and bacterial infections (interleukins) RBC production (erythropoietin) Stimulates growth and production of IGF1 (GH) Stimulates milk production (prolactin) Receptorlike Tyrosine Phosphatase Signaling molecules that activate these receptors have not yet been identified. Some may bind to adjacent cells and mediate cellcell adhesion Cytoplasmic tyrosine phosphatases show way more substrate specificity than do ser/thr phosphatases has SH2 domains and SHP1 and SHP2 substrate specific Crosses membrane a single time Receptor Serine/Threonine Kinases (TGFβ family) Regulate pattern formation (development; morphogens), proliferation, cell death, extracellular matrix formation 1. Signaling molecule binds to and activates type II receptor 2. Type II receptor recruits and activates Type I receptor (activates kinase activity) 3. Type I receptor then recruits Smad protein (latent transcription factor), and phosphorylates it Smad does not bind to phosphorylated amino acid on receptor 4. Phosphorylated Smad dissociates from receptor and binds coSmad 4, and then translocates to nucleus, where it activates target genes (transcription factor) Smad + Smad 4 = tetramer Summary: Receptor Tyrosine Kinase: Tyr; multiple signaling cascades and transcription regulation Tyrosine Kinaseassociated Receptors: Tyr; only transcription regulation Receptor Ser/Thr Kinase: Ser/Thr; only transcription regulation Receptor Guanylyl Cyclase Receptor is activated by natriuretic peptides (these peptides dilate blood vessels) Soluble guanylyl cyclase activated by nitric oxide (NO) Generated from nitroglycerine (angina) Maintains meiotic arrest in oocytes PDE, Viagra, ion channels, vision, PK GTP cGMP + PPi 5’GMP o Inhibited by Viagra Notch receptor Requires regulated proteolysis Notch receptor and its ligand (Delta is the ligand in this case) play a major role in development of most tissues Nerve cell development in Drosophila: When a committed cell in epithelium begins to develop as a neural cell, it inhibits neighboring cells from becoming neurons. Nerve cells express Delta signal on surface that binds to Notch receptor on adjacent epithelial cell. When the epithelial cell receptor attaches the delta ligand, it is prevented from becoming a neuronal cell. o Contact dependent 1. Binding of signal and receptor triggers 2 proteolytic events. 1) Cut receptor at surface of epithelial cell, 2) γ secretase cuts off notch tail γ secretase complex includes Presenilin1 and other proteinss 2. Notch tail moves into nucleus (as a transcription factor) to activate Notchresponsive genes, converting a repressor (CSL/CBF1) into an activator (acting as a coactivator) In flies, however, gene product blocks expression of proteins required for formation of neurons Alzheimer's: Presenilin1 is required for final cleavage to activate Notch. A mutation of presenilin1 causes cleavage of amyloid precursor protein (APP), a membrane protein expressed in neurons. Peptide fragment is released into extracellular space in brain, peptides accumulate and aggregate and form βamyloid plaques, believed to cause nerve damage. Regulated Proteolysis of βCatenin In the absence of the extracellular signaling molecule Wnt, β catenin is phosphorylated and targeted for proteosomal degradation In the presence of Wnt, Wnt binds to Frizzled receptor, leading to inactivation of GSK3b and accumulation of unphosphorylated (stabilized) βcatenin. βCatenin moves into nucleus and activates target genes. It functions as a coactivator of other transcription factors Hedgehog Signaling Pathway Requires regulated proteolysis In absence of hedgehog signal, Patched (active) keeps Smoothened inactive by cleaving Gli which acts to stop the transcription of hedgehog genes. In the presence of hedgehog signal: 1. Patched is internalized and degraded in the lysosomes. 2. Smoothened is phosphorylated by PKA and CK1 3. Smoothened is recruited to the plasma membrane 4. Gli is stabilized and released (not cleaved/damaged) 5. Gli translocated to nucleus where it is a transcription factor for hedgehog genes Pathway is involved in embryogenesis: lung, GI track, brain, skeleton, muscle, regulates stem cell proliferation and maintenance, cell polarity, proliferation Various cancers are caused by inappropriate expression of hedgehog Hedgehog inhibitor is in clinical trials for treatment of pancreatic cancer
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