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

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?

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

Did you know Bacteria can talk?

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

Hormones: diverse sizes,shapes
Gap junctions between animal cells 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 Plasmodesmata between plant cells (b) Cell-cell recognition

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

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

Fig 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 EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 Reception 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules in a signal transduction pathway Relay race Signaling molecule very similar pathways between yeast and bacteria mammals and plants Suggest early versions of signaling used before the 1st multicellular organism (1bya)

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)

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 Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

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

Epinephrine and glycogen phosphorylase and glycogen into tube = NO CATABOLISM
Infer: epinephrine must not interact directly with enzyme and needs intact cells (plasma membrane) Diseases involving phosphorylase, glycogen; muscle (McArdle syndrome, glycogen storage disease type V)

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

Signaling-molecule binding site
Fig. 11-7a Signaling-molecule binding site 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 Figure 11.7 Membrane receptors—G protein-coupled receptors, part 1 Segment that interacts with G proteins The G protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive G protein-coupled receptor

GTP high energy molecule
Fig. 11-7b GTP high energy molecule Yeast mating factors, epinephrine, hormones and neurotransmitters Plasma membrane G protein-coupled receptor Inactive enzyme Activated receptor Signaling molecule GDP G protein (inactive) Enzyme GDP GTP CYTOPLASM 1 2 Activated enzyme Figure 11.7 Membrane receptors—G protein-coupled receptors, part 2 GTP GDP P i Cellular response 3 4 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)

Tyrosine kinases are enzymatic: kinase transfers P
Fig. 11-7c Signaling molecule (ligand) Ligand-binding site Signaling molecule  Helix Tyr Tyr Tyrosines Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Receptor tyrosine kinase proteins Dimer CYTOPLASM 1 Tyrosine kinases are enzymatic: kinase transfers P 2 One tyr complex can activate more than 10 diff cellular responses Activated relay proteins Cellular response 1 Tyr Tyr P Tyr Tyr P Tyr P Tyr P Tyr Tyr P Tyr Tyr P Tyr Tyr P P Tyr Tyr P Tyr Tyr P P Tyr Tyr P Cellular response 2 6 ATP 6 ADP Activated tyrosine kinase regions Fully activated receptor tyrosine kinase Inactive relay proteins 3 4

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

A ligand-gated ion channel receptor acts as a gate when
Fig. 11-7d 1 Signaling molecule (ligand) Gate closed Ions 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 Plasma membrane Ligand-gated ion channel receptor 2 Gate open 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 Cellular response 3 Gate closed

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

Hormone (testosterone) Plasma membrane Receptor protein Hormone-
Fig Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.8 Steroid hormone interacting with an intracellular receptor mRNA NUCLEUS New protein CYTOPLASM

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

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

Phosphorylation cascade
Fig. 11-9 Signaling molecule Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation Receptor Activated relay molecule Inactive protein kinase 1 Active protein kinase 1 This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off Inactive protein kinase 2 ATP Phosphorylation cascade ADP Active protein kinase 2 P PP P i Protein phosphatases remove the phosphates from proteins, a process called dephosphorylation Figure 11.9 A phosphorylation cascade Inactive protein kinase 3 ATP ADP Active protein kinase 3 P PP P i Inactive protein ATP ADP P Active protein Cellular response PP P i

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

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

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

Calcium ions (Ca2+) act as a second messenger in many pathways
Fig EXTRACELLULAR FLUID Plasma membrane Ca2+ pump ATP Calcium ions (Ca2+) act as a second messenger in many pathways Mitochondrion Calcium is an important second messenger because cells can regulate its concentration Nucleus CYTOSOL Ca2+ pump Endoplasmic reticulum (ER) Figure The maintenance of calcium ion concentrations in an animal cell Ca2+ pump ATP Key High [Ca2+] Low [Ca2+]

Animation: Signal Transduction Pathways
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 (IP3) and diacylglycerol (DAG) as additional second messengers Animation: Signal Transduction Pathways Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein
Fig EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Figure Calcium and IP3 in signaling pathways Endoplasmic reticulum (ER) Various proteins activated Cellular responses Ca2+ Ca2+ (second messenger) CYTOSOL

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

Ultimately, leads to regulation of one or more cellular activities
Fig 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 Growth factor Reception Receptor Response: Cell signaling leads to regulation of transcription or cytoplasmic activities Phosphorylatin cascade Transduction The cell’s response to an extracellular signal is sometimes called the “output response CYTOPLASM Inactive transcription factor Active transcription factor Figure Nuclear responses to a signal: the activation of a specific gene by a growth factor Response P DNA Gene NUCLEUS mRNA

Glucose-1-phosphate (108 molecules)
Fig Reception Binding of epinephrine to G protein-coupled receptor (1 molecule) Transduction Inactive G protein Active G protein (102 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (102) ATP Cyclic AMP (104) Inactive protein kinase A Active protein kinase A (104) Figure Cytoplasmic response to a signal: the stimulation of glycogen breakdown by epinephrine Inactive phosphorylase kinase Active phosphorylase kinase (105) Inactive glycogen phosphorylase Active glycogen phosphorylase (106) Response Glycogen Glucose-1-phosphate (108 molecules)

Fig RESULTS Wild-type (shmoos) ∆Fus3 ∆formin CONCLUSION Mating factor 1 Shmoo projection forming G protein-coupled receptor Formin P Fus3 Actin subunit Figure How do signals induce directional cell growth in yeast? GTP P GDP 2 Phosphory- lation cascade Formin Formin P 4 Microfilament Fus3 Fus3 P 5 3

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

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

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

Figure 11.17 The specificity of cell signaling
molecule Receptor Relay molecules Response 1 Response 2 Response 3 Cell A. Pathway leads to a single response. Cell B. Pathway branches, leading to two responses. Figure The specificity of cell signaling Activation or inhibition Response 4 Response 5 Cell C. Cross-talk occurs between two pathways. Cell D. Different receptor leads to a different response.

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

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

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

Fig Figure Apoptosis of human white blood cells 2 µm

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

Figure 11.20 Molecular basis of apoptosis in C. elegans
Ced-9 protein (active) inhibits Ced-4 activity Mitochondrion Ced-4 Ced-3 Receptor for death- signaling molecule Inactive proteins (a) No death signal Ced-9 (inactive) Cell forms blebs Death- signaling molecule Figure Molecular basis of apoptosis in C. elegans Active Ced-4 Active Ced-3 Other proteases Nucleases Activation cascade (b) Death signal

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

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

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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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:

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