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Cell Signaling Ch 11 There are three main receptorsin the p.m. for signaling pathways, G-protein coupled receptors, Tyrosine-kinase receptors second messengers.

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Presentation on theme: "Cell Signaling Ch 11 There are three main receptorsin the p.m. for signaling pathways, G-protein coupled receptors, Tyrosine-kinase receptors second messengers."— Presentation transcript:

1 Cell Signaling Ch 11 There are three main receptorsin the p.m. for signaling pathways, G-protein coupled receptors, Tyrosine-kinase receptors second messengers (cAMP, Ca2+, and IP3); –discuss all in terms of the three stages of cell signaling- »1. reception, »2. transduction »3. response (don't forget to discuss the importance of protein phosphorylation Discuss the importance of cell signaling in nerve impulse transmission. Intracellular receptors Discuss the importance of cell communication used by the endocrine system, is there any overlap with the nervous system? What role does cell signaling play in apoptosis? When and where is apoptosis appropriate?

2 External signals are converted to responses within the cell Saccharomyces cerevisiae mating between alpha and beta cells using chemical signals

3 Did you know Bacteria can talk?

4 Bacteria Quorum Bacteria sense density of bacteria populations by detecting concentration of chemicals –Inter species –Intra species –All bacteria have the same chemical (old) **Allows for coordination of activity bioluminescence biofilm

5 Hormones: diverse sizes,shapes Animals: endocrine signaling (gland >circulatory>target) Plant growth regulators: may travel in vessels but usually move through cells or diffuse through air as a gas Gap junctions between animal cells Plasmodesmata between plant cells (b) Cell-cell recognition

6 Fig. 11-5ab Local signaling Target cell Secretory vesicle Secreting cell Local regulator diffuses through extracellular fluid (a) Paracrine signaling (b) Synaptic signaling Target cell is stimulated Neurotransmitter diffuses across synapse Electrical signal along nerve cell triggers release of neurotransmitter Growth hormones are local regulators Ach is signal ligand for muscle action potential )allows Na) to rush in

7 Fig. 11-5c Long-distance signaling Endocrine cell Blood vessel Hormone travels in bloodstream to target cells Target cell (c) Hormonal signaling Long Distance signaling: hormones and nerves

8 Fig EXTRACELLULAR FLUID Plasma membrane CYTOPLASM Receptor Signaling molecule Relay molecules in a signal transduction pathway Activation of cellular response Reception TransductionResponse Signal Transduction Pathway: process; how an external signal binds to cell’s surface is converted to a specific cellular response thru a series of steps very similar pathways between yeast and bacteria mammals and plants Suggest early versions of signaling used before the 1st multicellular organism (1bya) Relay race

9 What happens when a cell encounters a ligand (signaling molecule)? 1. molecule must be recognized by a specific receptor 2. Signal (info being carried) must be changed into another form (TRANSDUCED) 3. inside cell (AMPLIFY, DIVERSIFY)

10 The Three Stages of Cell Signaling: A Preview Earl W. Sutherland discovered how the hormone epinephrine acts on cells Sutherland suggested that cells receiving signals went through three processes: –Reception –Transduction –Response Animation: Overview of Cell Signaling Animation: Overview of Cell Signaling Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

11 Sutherland: epinephrine Epinephrine: breaks down glycogen (liver, muscle) releasing glucose 1P and glucose 6P Can make ATP in liver or remove P and glucose can enter bloodstream

12 Epinephrine and glycogen phosphorylase and glycogen into tube = NO CATABOLISM Infer: epinephrine must not interact directly with enzyme and needs intact cells (plasma membrane) pt/bcbp/molbiochem/ MBWeb/mb1/part2/gl ycogen.htmhttp://www.rpi.edu/de pt/bcbp/molbiochem/ MBWeb/mb1/part2/gl ycogen.htm Diseases involving phosphorylase, glycogen; muscle (McArdle syndrome, glycogen storage disease type V)

13 Receptors in the Plasma Membrane Most water-soluble signal molecules bind to specific sites on receptor proteins in the plasma membrane 3 main types of membrane receptors: –G protein-coupled receptors –Receptor tyrosine kinases –Ion channel receptors Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

14 Fig. 11-7a Signaling-molecule binding site Segment that interacts with G proteins G protein-coupled receptor The G protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive Although receptors vary in binding sites for ligands and diff G proteins Similar structure with 7 alpha helices Evidence evolved early due to the presence in diverse organisms

15 Fig. 11-7b G protein-coupled receptor Plasma membrane Enzyme G protein (inactive) GDP CYTOPLASM Activated enzyme GTP Cellular response GDP P i Activated receptor GDP GTP Signaling molecule Inactive enzyme GTP high energy molecule Yeast mating factors, epinephrine, hormones and neurotransmitters G coupled receptor systems diverse: embryonic development, sensory reception, (vision and smell) Whooping cough, cholera, botulism make people sick by making toxins that interfere with G protein function (60% drugs are for G protiens)

16 Fig. 11-7c Signaling molecule (ligand) Ligand-binding site  Helix Tyrosines Tyr Receptor tyrosine kinase proteins CYTOPLASM Signaling molecule Tyr Dimer Activated relay proteins Tyr P P P P P P Cellular response 1 Cellular response 2 Inactive relay proteins Activated tyrosine kinase regions Fully activated receptor tyrosine kinase 6 6 ADP ATP Tyr P P P P P P Tyrosine kinases are enzymatic: kinase transfers P One tyr complex can activate more than 10 diff cellular responses

17 Tyrosine Kinases More than one signal transduction pathway can be triggered at once Allows for cell regulation and coordination for growth and repro A single ligand binding event can trigger multiple pathways = *** key difference between tyr kinase and G proteins Tyr kinase abnormalities can lead to cancer

18 Fig. 11-7d Signaling molecule (ligand) Gate closed Ions Ligand-gated ion channel receptor Plasma membrane Gate open Cellular response Gate closed A ligand-gated ion channel receptor acts as a gate when the receptor changes shape When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as Na+ or Ca2+, through a channel in the receptor Ligand gated ion channels are very important in nervous system NT released form the presynaptoc cell are ligands for the Na channels on the post synaptic cell in order to start an daciton potential

19 Intracellular Receptors Some receptor proteins are intracellular, found in the cytosol or nucleus of target cells Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors Examples of hydrophobic messengers are the steroid and thyroid hormones of animals An activated hormone-receptor complex can act as a transcription factor, turning on specific genes Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

20 Fig Hormone (testosterone) EXTRACELLULAR FLUID Receptor protein Plasma membrane Hormone- receptor complex DNA mRNA NUCLEUS New protein CYTOPLASM

21 Concept 11.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell Signal transduction usually involves multiple steps Multistep pathways can amplify a signal: A few molecules can produce a large cellular response Multistep pathways provide more opportunities for coordination and regulation of the cellular response Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

22 Signal Transduction Pathways The molecules that relay a signal from receptor to response are mostly proteins Like falling dominoes, the receptor activates another protein, which activates another, and so on, until the protein producing the response is activated At each step, the signal is transduced into a different form, usually a shape change in a protein Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

23 Fig Signaling molecule Receptor Activated relay molecule Inactive protein kinase 1 Active protein kinase 1 Inactive protein kinase 2 ATP ADP Active protein kinase 2 P P PP Inactive protein kinase 3 ATP ADP Active protein kinase 3 P P PP i ATP ADP P Active protein PP P i Inactive protein Cellular response Phosphorylation cascade i Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation Protein phosphatases remove the phosphates from proteins, a process called dephosphorylation This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off

24 Small Molecules and Ions as Second Messengers The extracellular signal molecule that binds to the receptor is a pathway’s “first messenger” Second messengers are small, nonprotein, water-soluble molecules or ions that spread throughout a cell by diffusion Second messengers participate in pathways initiated by G protein-coupled receptors and receptor tyrosine kinases Cyclic AMP and calcium ions are common second messengers Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

25 Adenylyl cyclase Fig Pyrophosphate P P i ATP cAMP Phosphodiesterase AMP Cyclic AMP (cAMP) is one of the most widely used second messengers Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response to an extracellular signal

26 First messenger Fig G protein Adenylyl cyclase GTP ATP cAMP Second messenger Protein kinase A G protein-coupled receptor Cellular responses Many signal molecules trigger formation of cAMP Other components of cAMP pathways are G proteins, G protein- coupled receptors, and protein kinases cAMP usually activates protein kinase A, which phosphorylates various other proteins Further regulation of cell metabolism is provided by G-protein systems that inhibit adenylyl cyclase

27 EXTRACELLULAR FLUID Fig ATP Nucleus Mitochondrion Ca 2+ pump Plasma membrane CYTOSOL Ca 2+ pump Endoplasmic reticulum (ER) Ca 2+ pump ATP Key High [Ca 2+ ] Low [Ca 2+ ] Calcium ions (Ca2+) act as a second messenger in many pathways Calcium is an important second messenger because cells can regulate its concentration

28 A signal relayed by a signal transduction pathway may trigger an increase in calcium in the cytosol Pathways leading to the release of calcium involve inositol triphosphate (IP 3 ) and diacylglycerol (DAG) as additional second messengers Animation: Signal Transduction Pathways Animation: Signal Transduction Pathways Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

29 Fig G protein EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein-coupled receptor Phospholipase C PIP 2 DAG IP 3 (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) Ca 2+ CYTOSOL Various proteins activated Cellular responses Ca 2+ (second messenger ) GTP

30 Signaling pathways : Output Response Nuclear or cytoplasmic responses Regulate the activity of other enzymes can affect the physical characteristics of a cell, for example, cell shape

31 Fig Growth factor Receptor Phosphorylatin cascade Reception Transduction Active transcription factor Response P Inactive transcription factor CYTOPLASM DNA NUCLEUS mRNA Gene Response: Cell signaling leads to regulation of transcription or cytoplasmic activities The cell’s response to an extracellular signal is sometimes called the “output response Ultimately, leads to regulation of one or more cellular activities The response may occur in the cytoplasm or may involve action in the nucleus Many signaling pathways regulate the synthesis of enzymes or other proteins, usually by turning genes on or off in the nucleus The final activated molecule may act as a transcription factor

32 Fig Reception Transduction Response Binding of epinephrine to G protein-coupled receptor (1 molecule) Inactive G protein Active G protein (10 2 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (10 2 ) ATP Cyclic AMP (10 4 ) Inactive protein kinase A Active protein kinase A (10 4 ) Inactive phosphorylase kinase Active phosphorylase kinase (10 5 ) Inactive glycogen phosphorylase Active glycogen phosphorylase (10 6 ) Glycogen Glucose-1-phosphate (10 8 molecules)

33 Fig RESULTS CONCLUSION Wild-type (shmoos)∆Fus3∆formin Shmoo projection forming Formin P Actin subunit P P Formin Fus3 Phosphory- lation cascade GTP G protein-coupled receptor Mating factor GDP Fus3 P Microfilament

34 Fine-Tuning of the Response Multistep pathways have two important benefits: –Amplifying the signal (and thus the response) –Contributing to the specificity of the response Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

35 Signal Amplification Enzyme cascades amplify the cell’s response At each step, the number of activated products is much greater than in the preceding step Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

36 The Specificity of Cell Signaling and Coordination of the Response Different kinds of cells have different collections of proteins These different proteins allow cells to detect and respond to different signals Even the same signal can have different effects in cells with different proteins and pathways Pathway branching and “cross-talk” further help the cell coordinate incoming signals Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

37 Fig Signaling molecule Receptor Relay molecules Response 1 Cell A. Pathway leads to a single response. Response 2 Response 3 Cell B. Pathway branches, leading to two responses. Response 4 Response 5 Activation or inhibition Cell C. Cross-talk occurs between two pathways. Cell D. Different receptor leads to a different response.

38 Fig Signaling molecule Receptor Scaffolding protein Plasma membrane Three different protein kinases Signaling Efficiency: Scaffolding Proteins and Signaling Complexes Scaffolding proteins can increase the signal transduction efficiency by grouping together different proteins involved in the same pathway Scaffolding proteins are large relay proteins to which other relay proteins are attached

39 Termination of the Signal Inactivation mechanisms are an essential aspect of cell signaling When signal molecules leave the receptor, the receptor reverts to its inactive state Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

40 Concept 11.5: Apoptosis (programmed cell death) integrates multiple cell-signaling pathways Apoptosis is programmed or controlled cell suicide A cell is chopped and packaged into vesicles that are digested by scavenger cells Apoptosis prevents enzymes from leaking out of a dying cell and damaging neighboring cells Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

41 Fig µm

42 Apoptosis in the Soil Worm Caenorhabditis elegans Apoptosis is important in shaping an organism during embryonic development The role of apoptosis in embryonic development was first studied in Caenorhabditis elegans In C. elegans, apoptosis results when specific proteins that “accelerate” apoptosis override those that “put the brakes” on apoptosis Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

43 Fig Ced-9 protein (active) inhibits Ced-4 activity Mitochondrion Receptor for death- signaling molecule Ced-4 Ced-3 Inactive proteins (a) No death signal Ced-9 (inactive) Cell forms blebs Death- signaling molecule Other proteases Active Ced-4 Active Ced-3 Nucleases Activation cascade (b) Death signal

44 Apoptotic Pathways and the Signals That Trigger Them Caspases are the main proteases (enzymes that cut up proteins) that carry out apoptosis Apoptosis can be triggered by: –An extracellular death-signaling ligand –DNA damage in the nucleus –Protein misfolding in the endoplasmic reticulum Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

45 Fig Interdigital tissue 1 mm Apoptosis evolved early in animal evolution and is essential for the development and maintenance of all animals Apoptosis may be involved in some diseases (for example, Parkinson’s and Alzheimer’s); interference with apoptosis may contribute to some cancers


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