Cell Communication Cell-to-cell communication is essential for multicellular organisms Biologists have discovered some universal mechanisms of cellular regulation The combined effects of multiple signals determine cell response For example, the dilation of blood vessels is controlled by multiple molecules Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-1 Microbes are a window on the role of cell signaling in the evolution of life Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings A signal transduction pathway is a series of steps by which a signal on a cells surface is converted into a specific cellular response Signal transduction pathways convert signals on a cells surface into cellular responses Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig Receptor factor a factor a a Exchange of mating factors Yeast cell, mating type a Yeast cell, mating type Mating New a/ cell a/ 1 2 3 Pathway similarities suggest that ancestral signaling molecules evolved in prokaryotes and were modified later in eukaryotes The concentration of signaling molecules allows bacteria to detect population density Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig Individual rod- shaped cells Spore-forming structure (fruiting body) Aggregation in process Fruiting bodies 0.5 mm 1 3 2 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 Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig Plasma membranes Gap junctions between animal cells (a) Cell junctions Plasmodesmata between plant cells (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 Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig Local signaling Target cell Secreting cell Secretory vesicle 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 Long-distance signaling Endocrine cell Blood vessel Hormone travels in bloodstream to target cells Target cell (c) Hormonal signaling 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 Fig. 11-5c Long-distance signaling Endocrine cell Blood vessel Hormone travels in bloodstream to target cells Target cell (c) Hormonal signaling 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 Fig Reception 1 EXTRACELLULAR FLUID Signaling molecule Plasma membrane CYTOPLASM 1 Receptor Fig EXTRACELLULAR FLUID Signaling molecule Plasma membrane CYTOPLASM Transduction 2 Relay molecules in a signal transduction pathway Reception 1 Receptor Fig EXTRACELLULAR FLUID Plasma membrane CYTOPLASM Receptor Signaling molecule Relay molecules in a signal transduction pathway Activation of cellular response TransductionResponse 2 3 Reception 1 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 Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Most water-soluble signal molecules bind to specific sites on receptor proteins in the plasma membrane There are three 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 A G protein-coupled receptor 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 Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-7a Signaling-molecule binding site Segment that interacts with G proteins G protein-coupled receptor 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 Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines A receptor tyrosine kinase can trigger multiple signal transduction pathways at once Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings 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 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 Ca 2+, through a channel in the receptor Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 11-7d Signaling molecule (ligand) Gate closed Ions Ligand-gated ion channel receptor Plasma membrane Gate open Cellular response Gate closed 3 2 1 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 Fig Hormone (testosterone) Receptor protein Plasma membrane EXTRACELLULAR FLUID DNA NUCLEUS CYTOPLASM Fig Receptor protein Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Hormone- receptor complex DNA NUCLEUS CYTOPLASM Fig Hormone (testosterone) EXTRACELLULAR FLUID Receptor protein Plasma membrane Hormone- receptor complex DNA NUCLEUS CYTOPLASM Fig Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA mRNA NUCLEUS CYTOPLASM Fig Hormone (testosterone) EXTRACELLULAR FLUID Receptor protein Plasma membrane Hormone- receptor complex DNA mRNA NUCLEUS New protein CYTOPLASM 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 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 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 Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings 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 Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings 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 The extracellular signal molecule that binds to the receptor is a pathways 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 Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response to an extracellular signal Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Adenylyl cyclase Fig Pyrophosphate P P i ATP cAMP Phosphodiesterase 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 Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings First messenger Fig G protein Adenylyl cyclase GTP ATP cAMP Second messenger Protein kinase A G protein-coupled receptor Cellular responses Calcium ions (Ca 2+ ) act as a second messenger in many pathways Calcium is an important second messenger because cells can regulate its concentration Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings 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+ ] 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 Fig EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein GTP G protein-coupled receptor Phospholipase C PIP 2 IP 3 DAG (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) Ca 2+ CYTOSOL 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 Ca 2+ (second messenger ) GTP 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 The cells response to an extracellular signal is sometimes called the output response Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Ultimately, a signal transduction pathway 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 function as a transcription factor Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig Growth factor Receptor Phosphorylatio n cascade Reception Transduction Active transcription factor Response P Inactive transcription factor CYTOPLASM DNA NUCLEUS mRNA Gene Other pathways regulate the activity of enzymes Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings 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) Signaling pathways can also affect the physical characteristics of a cell, for example, cell shape Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig RESULTS CONCLUSION Wild-type (shmoos)Fus3formin 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 Fig a RESULTS Wild-type (shmoos) Fus3 formin Fig b CONCLUSION Mating factor G protein-coupled receptor GDP GTP Phosphory- lation cascade Shmoo projection forming Fus3 Formin P P P P Actin subunit Microfilament 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 Enzyme cascades amplify the cells 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 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 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. Fig a Signaling molecule Receptor Relay molecules Response 1 Cell A. Pathway leads to a single response. Cell B. Pathway branches, leading to two responses. Response 2 Response 3 Fig b Response 4Response 5 Activation or inhibition Cell C. Cross-talk occurs between two pathways. Cell D. Different receptor leads to a different response. 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 Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig Signaling molecule Receptor Scaffolding protein Plasma membrane Three different protein kinases 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 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 m 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 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 Fig a Ced-9 protein (active) inhibits Ced-4 activity Mitochondrion Ced-4Ced-3 Receptor for death- signaling molecule Inactive proteins (a) No death signal Fig b (b) Death signal Death- signaling molecule Ced-9 (inactive) Cell forms blebs Active Ced-4 Active Ced-3 Activation cascade Other proteases Nucleases 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 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, Parkinsons and Alzheimers); interference with apoptosis may contribute to some cancers Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig Interdigital tissue 1 mm Fig. 11-UN1 Reception Transduction Response Receptor Relay molecules Signaling molecule Activation of cellular response 1 2 3 Fig. 11-UN2 1. Describe the nature of a ligand-receptor interaction and state how such interactions initiate a signal- transduction system 2. Compare and contrast G protein-coupled receptors, tyrosine kinase receptors, and ligand-gated ion channels 3. List two advantages of a multistep pathway in the transduction stage of cell signaling 4. Explain how an original signal molecule can produce a cellular response when it may not even enter the target cell Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings 5. Define the term second messenger; briefly describe the role of these molecules in signaling pathways 6. Explain why different types of cells may respond differently to the same signal molecule 7. Describe the role of apoptosis in normal development and degenerative disease in vertebrates Copyright 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings