Cell Communication PDF

CELL COMMUNICATION Overview: Cellular Messaging Cell-to-cell communication is essential for both multicellular and unicellular organisms Biologists have discovered some universal mechanisms of cellular regulation Cells most often communicate with each other...

CELL COMMUNICATION Overview: Cellular Messaging Cell-to-cell communication is essential for both multicellular and unicellular organisms Biologists have discovered some universal mechanisms of cellular regulation Cells most often communicate with each other via chemical signals For example, the fight-or-flight response is triggered by a signaling molecule called epinephrine © 2011 Pearson Education, Inc. Figure 11.1  External signals are converted to responses within the cell Microbes provide a glimpse of the role of cell signaling in the evolution of life © 2011 Pearson Education, Inc. Evolution of Cell Signaling The yeast, Saccharomyces cerevisiae, has two mating types, a and α Cells of different mating types locate each other via secreted factors specific to each type A signal transduction pathway is a series of steps by which a signal on a cell’s surface is converted into a specific cellular response Signal transduction pathways convert signals on a cell’s surface into cellular responses © 2011 Pearson Education, Inc. Figure 11.2 Receptor α factor 1 Exchange of mating factors a α a factor Yeast cell, Yeast cell, mating type a mating type α 2 Mating a α 3 New a/α cell a/α  Pathway similarities suggest that ancestral signaling molecules evolved in prokaryotes and were modified later in eukaryotes The concentration of signaling molecules allows bacteria to sense local population density © 2011 Pearson Education, Inc. Figure 11.3 1 Individual rod-shaped cells 2 Aggregation 0.5 mm in progress 3 Spore-forming structure (fruiting body) 2.5 mm Fruiting bodies Figure 11.3a 1 Individual rod-shaped cells Figure 11.3b 2 Aggregation in progress Figure 11.3c 0.5 mm 3 Spore-forming structure (fruiting body) Figure 11.3d 2.5 mm Fruiting bodies Local and Long-Distance Signaling Cells in a multicellular organism communicate by chemical messengers Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacent cells In local signaling, animal cells may communicate by direct contact, or cell-cell recognition © 2011 Pearson Education, Inc. Figure 11.4 Plasma membranes Gap junctions Plasmodesmata between animal cells between plant cells (a) Cell junctions (b) Cell-cell recognition  In many other cases, animal cells communicate using local regulators, messenger molecules that travel only short distances In long-distance signaling, plants and animals use chemicals called hormones The ability of a cell to respond to a signal depends on whether or not it has a receptor specific to that signal © 2011 Pearson Education, Inc.  Paracrine signalling is a form of cell signalling or cell-to-cell communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells.  Endocrine signalling occurs between distant cells and is mediated by hormones released from specific endocrine cells that travel to target cells, producing a slower, long-lasting response.  Synaptic signalling is similar to paracrine signalling but there is a special structure called the synapse between the cell originating and the cell receiving the signal. Synaptic signalling only occurs between cells with the synapse; for example between a neuron and the muscle that is controlled by neural activity. Figure 11.5 Local signaling Long-distance signaling Target cell Electrical signal Endocrine cell along nerve cell Blood triggers release of vessel neurotransmitter. Neurotransmitter Secreting Secretory diffuses across cell vesicle synapse. Hormone travels in bloodstream. Target cell Local regulator specifically diffuses through Target cell binds extracellular fluid. is stimulated. hormone. (a) Paracrine signaling (b) Synaptic signaling (c) Endocrine (hormonal) signaling Figure 11.5a Local signaling Target cell Electrical signal along nerve cell triggers release of neurotransmitter. Neurotransmitter Secreting Secretory diffuses across cell vesicle synapse. Local regulator diffuses through Target cell extracellular fluid. is stimulated. (a) Paracrine signaling (b) Synaptic signaling Figure 11.5b Long-distance signaling Endocrine cell Blood vessel Hormone travels in bloodstream. Target cell specifically binds hormone. (c) Endocrine (hormonal) signaling 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 © 2011 Pearson Education, Inc.  Animation: Overview of Cell Signaling Right-click slide / select “Play” © 2011 Pearson Education, Inc. Figure 11.6-1 EXTRACELLULAR CYTOPLASM FLUID Plasma membrane 1 Reception Receptor Signaling molecule Figure 11.6-2 EXTRACELLULAR CYTOPLASM FLUID Plasma membrane 1 Reception 2 Transduction Receptor Relay molecules in a signal transduction pathway Signaling molecule Figure 11.6-3 EXTRACELLULAR CYTOPLASM FLUID Plasma membrane 1 Reception 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules in a signal transduction pathway Signaling molecule Concept 11.2: Reception: A signaling molecule binds to a receptor protein, causing it to change shape The binding between a signal molecule (ligand) and receptor is highly specific A shape change in a receptor is often the initial transduction of the signal Most signal receptors are plasma membrane proteins © 2011 Pearson Education, Inc. Receptors in the Plasma Membrane Most water-soluble signal molecules bind to specific sites on receptor proteins that span the plasma membrane There are three main types of membrane receptors – G protein-coupled receptors – Receptor tyrosine kinases – Ion channel receptors © 2011 Pearson Education, Inc.  G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors A GPCR is a plasma membrane receptor that works with the help of a G protein The G protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive © 2011 Pearson Education, Inc. Figure 11.7a Signaling molecule binding site Segment that interacts with G proteins G protein-coupled receptor Figure 11.7b G protein-coupled Plasma Activated Signaling Inactive receptor membrane receptor molecule enzyme GTP GDP GDP CYTOPLASM G protein Enzyme GDP GTP 1 (inactive) 2 Activated enzyme GTP GDP Pi 3 Cellular response 4 Figure 11.8 β2-adrenergic Molecule receptors resembling ligand Plasma membrane Cholesterol  Receptor tyrosine kinases (RTKs) are membrane receptors that attach phosphates to tyrosines A receptor tyrosine kinase can trigger multiple signal transduction pathways at once Abnormal functioning of RTKs is associated with many types of cancers © 2011 Pearson Education, Inc. Figure 11.7c Signaling Ligand-binding site molecule (ligand) α helix in the Signaling membrane molecule Tyr Tyr Tyr Tyr Tyr Tyrosines Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr CYTOPLASM Receptor tyrosine Dimer kinase proteins 1 (inactive monomers) 2 Activated relay proteins Cellular P Tyr Tyr P Tyr Tyr P Tyr Tyr P response 1 Tyr Tyr P Tyr Tyr P P Tyr Tyr P Tyr Tyr P Tyr Tyr P P Tyr Tyr P Cellular 6 ATP 6 ADP response 2 Activated tyrosine Fully activated kinase regions receptor tyrosine (unphosphorylated kinase Inactive dimer) (phosphorylated relay proteins 3 4 dimer)  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 © 2011 Pearson Education, Inc. Figure 11.7d 1 2 3 Gate closed Ions Gate Gate closed Signaling open molecule (ligand) Plasma Ligand-gated membrane ion channel receptor Cellular response Intracellular Receptors Intracellular receptor proteins are 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 © 2011 Pearson Education, Inc. Figure 11.9-1 Hormone EXTRACELLULAR (testosterone) FLUID Plasma membrane Receptor protein DNA NUCLEUS CYTOPLASM Figure 11.9-2 Hormone EXTRACELLULAR (testosterone) FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA NUCLEUS CYTOPLASM Figure 11.9-3 Hormone EXTRACELLULAR (testosterone) FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA NUCLEUS CYTOPLASM Figure 11.9-4 Hormone EXTRACELLULAR (testosterone) FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA mRNA NUCLEUS CYTOPLASM Figure 11.9-5 Hormone EXTRACELLULAR (testosterone) FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA 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 © 2011 Pearson Education, Inc. 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 © 2011 Pearson Education, Inc. Protein Phosphorylation and Dephosphorylation In many pathways, the signal is transmitted by a cascade of protein phosphorylations Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation © 2011 Pearson Education, Inc.  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 or up or down, as required © 2011 Pearson Education, Inc. Figure 11.10 Signaling molecule Receptor Activated relay molecule Inactive protein kinase 1 Active protein kinase 1 Inactive protein kinase ATP 2 ADP P Active protein PP kinase Pi 2 Inactive protein kinase ATP 3 ADP P Active protein PP kinase Pi 3 Inactive protein ATP ADP P Active Cellular PP protein response Pi Figure 11.10a Activated relay molecule Inactive protein kinase 1 Active protein kinase 1 Inactive protein kinase ATP 2 ADP P Active protein PP kinase Pi 2 Inactive protein kinase ATP ADP P 3 Active protein PP kinase Pi 3 Inactive protein ATP ADP P Active protein PP Pi Small Molecules and Ions as Second Messengers The extracellular signal molecule (ligand) 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 GPCRs and RTKs Cyclic AMP and calcium ions are common second messengers © 2011 Pearson Education, Inc. Cyclic 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 © 2011 Pearson Education, Inc. Figure 11.11 Adenylyl cyclase Phosphodiesterase Pyrophosphate H2O P Pi ATP cAMP AMP Figure 11.11a Adenylyl cyclase Pyrophosphate P Pi ATP cAMP Figure 11.11b Phosphodiesterase H2O H2O cAMP AMP  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 © 2011 Pearson Education, Inc. Figure 11.12 First messenger (signaling molecule such as epinephrine) Adenylyl G protein cyclase G protein-coupled GTP receptor ATP Second cAMP messenger Protein kinase A Cellular responses Calcium Ions and Inositol Triphosphate (IP3) Calcium ions (Ca2+) act as a second messenger in many pathways Calcium is an important second messenger because cells can regulate its concentration © 2011 Pearson Education, Inc. Figure 11.13 EXTRACELLULAR Plasma FLUID membrane Ca2+ ATP pump Mitochondrion Nucleus CYTOSOL Ca2+ pump Endoplasmic Ca2+ reticulum ATP pump (ER) Key High [Ca2+ ] Low [Ca2+ ]  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 © 2011 Pearson Education, Inc.  Animation: Signal Transduction Pathways Right-click slide / select “Play” © 2011 Pearson Education, Inc. Figure 11.14-1 EXTRA- CELLULAR Signaling molecule FLUID (first messenger) G protein DAG GTP G protein-coupled PIP2 Phospholipase C receptor IP3 (second messenger) IP3-gated calcium channel Endoplasmic Ca2+ reticulum (ER) CYTOSOL Figure 11.14-2 EXTRA- CELLULAR Signaling molecule FLUID (first messenger) G protein DAG GTP G protein-coupled PIP2 Phospholipase C receptor IP3 (second messenger) IP3-gated calcium channel Endoplasmic Ca2+ reticulum (ER) Ca2+ (second CYTOSOL messenger) Figure 11.14-3 EXTRA- CELLULAR Signaling molecule FLUID (first messenger) G protein DAG GTP G protein-coupled PIP2 Phospholipase C receptor IP3 (second messenger) IP3-gated calcium channel Various Cellular Endoplasmic Ca2+ proteins reticulum (ER) responses activated Ca2+ (second CYTOSOL messenger) Concept 11.4: 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” © 2011 Pearson Education, Inc. Nuclear and Cytoplasmic Responses Ultimately, a signal transduction pathway leads to regulation of one or more cellular activities The response may occur in the cytoplasm or 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 in the signaling pathway may function as a transcription factor © 2011 Pearson Education, Inc. Figure 11.15 Growth factor Reception Receptor Phosphorylation cascade Transduction CYTOPLASM Inactive Active transcription transcription factor factor Response P DNA Gene NUCLEUS mRNA  Other pathways regulate the activity of enzymes rather than their synthesis © 2011 Pearson Education, Inc. Figure 11.16 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) Inactive phosphorylase kinase Active phosphorylase kinase (105) Inactive glycogen phosphorylase Active glycogen phosphorylase (106) Response Glycogen Glucose 1-phosphate (108 molecules)  Signaling pathways can also affect the overall behavior of a cell, for example, changes in cell shape © 2011 Pearson Education, Inc. Figure 11.17 RESULTS Wild type (with shmoos) ∆Fus3 ∆formin CONCLUSION 1 Mating Mating Shmoo projection factor factor G protein-coupled forming activates receptor Formin receptor. P Fus3 Actin GTP P subunit GDP 2 G protein binds GTP Phosphory- and becomes activated. lation Formin Formin cascade P 4 Fus3 phos- phorylates formin, Microfilament Fus3 Fus3 activating it. P 5 Formin initiates growth of 3 Phosphorylation cascade microfilaments that form activates Fus3, which moves the shmoo projections. to plasma membrane. Figure 11.17a Wild type (with shmoos) Figure 11.17b ∆Fus3 Figure 11.17c ∆formin Fine-Tuning of the Response There are four aspects of fine-tuning to consider – Amplification of the signal (and thus the response) – Specificity of the response – Overall efficiency of response, enhanced by scaffolding proteins – Termination of the signal © 2011 Pearson Education, Inc. 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 © 2011 Pearson Education, Inc. 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 © 2011 Pearson Education, Inc. Figure 11.18 Signaling molecule Receptor Relay Activation molecules or inhibition Response 1 Response 2 Response 3 Response 4 Response 5 Cell A. Pathway leads Cell B. Pathway branches, Cell C. Cross-talk occurs Cell D. Different receptor to a single response. leading to two responses. between two pathways. leads to a different response. Figure 11.18a Signaling molecule Receptor Relay molecules Response 1 Response 2 Response 3 Cell A. Pathway leads Cell B. Pathway branches, to a single response. leading to two responses. Figure 11.18b Activation or inhibition Response 4 Response 5 Cell C. Cross-talk occurs Cell D. Different receptor between two pathways. leads to a different response. Signaling Efficiency: Scaffolding Proteins and Signaling Complexes Scaffolding proteins are large relay proteins to which other relay proteins are attached Scaffolding proteins can increase the signal transduction efficiency by grouping together different proteins involved in the same pathway In some cases, scaffolding proteins may also help activate some of the relay proteins © 2011 Pearson Education, Inc. Figure 11.19 Signaling Plasma molecule membrane Receptor Three different protein kinases Scaffolding protein Termination of the Signal Inactivation mechanisms are an essential aspect of cell signaling If ligand concentration falls, fewer receptors will be bound Unbound receptors revert to an inactive state © 2011 Pearson Education, Inc. Concept 11.5: Apoptosis integrates multiple cell-signaling pathways Apoptosis is programmed or controlled cell suicide Components of the cell are chopped up and packaged into vesicles that are digested by scavenger cells Apoptosis prevents enzymes from leaking out of a dying cell and damaging neighboring cells © 2011 Pearson Education, Inc. Figure 11.20 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 studied in Caenorhabditis elegans In C. elegans, apoptosis results when proteins that “accelerate” apoptosis override those that “put the brakes” on apoptosis © 2011 Pearson Education, Inc. Figure 11.21 Ced-9 protein (active) inhibits Ced-4 Ced-9 Cell activity (inactive) forms blebs Mitochondrion Death- signaling molecule Active Active Other Ced-4 Ced-3 proteases Ced-4 Ced-3 Nucleases Receptor Activation for death- Inactive proteins cascade signaling molecule (a) No death signal (b) Death signal Figure 11.21a Ced-9 protein (active) inhibits Ced-4 activity Mitochondrion Ced-4 Ced-3 Receptor for death- Inactive proteins signaling molecule (a) No death signal Figure 11.21b Ced-9 Cell (inactive) forms blebs Death- signaling molecule Active Active Other Ced-4 Ced-3 proteases Activation Nucleases 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 © 2011 Pearson Education, Inc.  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 © 2011 Pearson Education, Inc. Figure 11.22 Cells undergoing Space between Interdigital tissue apoptosis 1 mm digits Figure 11.22a Interdigital tissue Figure 11.22b Cells undergoing apoptosis Figure 11.22c Space between 1 mm digits Figure 11.UN01 1 Reception 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules Signaling molecule Figure 11.UN02