Chapter 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 called epinephrine Concept.: External signals are converted to responses within the cell Microbes provide a glimpse of the role of cell signaling in the evolution of life Evolution of Cell The yeast, Saccharomyces cerevisiae, have 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 4 Figure. Exchange of mating factors Mating a Yeast cell, mating type a a a factor α factor Yeast cell, mating type α α α athway similarities suggest that ancestral signaling s evolved in prokaryotes and were modified later in eukaryotes The concentration of signaling s allows bacteria to sense local population density New a/α cell a/α 5 6
Figure. Individual rod-shaped cells Spore-forming structure (fruiting body) 0.5 mm.5 mm Aggregation in progress Local and Long-Distance 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 Fruiting bodies 7 8 Figure.4 lasma s Gap junctions between animal cells (a) Cell junctions lasmodesmata between plant cells In many other cases, animal cells communicate using local regulators, messenger s 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 specific to that signal (b) Cell-cell recognition 9 0 Figure.5a Figure.5b Long-distance signaling Local signaling Target cell Electrical signal along nerve cell triggers release of neurotransmitter. Endocrine cell Blood vessel Secreting cell Secretory vesicle Neurotransmitter diffuses across synapse. Hormone travels in bloodstream. Local regulator diffuses through extracellular fluid. Target cell is stimulated. Target cell specifically binds hormone. (a) aracrine signaling (b) Synaptic signaling (c) Endocrine (hormonal) signaling
The Three Stages of Cell : A review Earl W. Sutherland discovered how the hormone epinephrine acts on cells Sutherland suggested that cells receiving signals went through three processes Reception Transduction Response Reception lasma CYTOLASM Figure.6- Reception: The signaling binds to the of the target cell s 4 lasma CYTOLASM lasma CYTOLASM Reception Transduction Reception Transduction Response Relay s in a signal transduction pathway Relay s in a signal transduction pathway Activation of cellular response Figure.6- Transduction: The signal is converted and relayed along a pathway 5 Figure.6- Response: The transduced signal triggers a specific cellular activities 6 Concept.: Reception: A signaling binds to a, causing it to change shape The binding between a signal (ligand) and is highly specific A shape change in a is often the initial transduction of the signal Most signal s are plasma s s in the lasma Membrane Most water-soluble signal s bind to specific sites on s that span the plasma There are three main types of s G -coupled s tyrosine kinases Ion channel s 7 8
Figure.7b G--coupled (GCRs) are the largest family of cellsurface s that work with the help of a G The G acts as an on/off switch Abnormal GCR system is related to diseases such as asthma, hypertension and heart disease Figure.7a 9 G -coupled CYTOLASM GD lasma G (inactive) GT Enzyme Activated enzyme Cellular response 4 Activated GD GT GD GD GT i enzyme 0 GCR Systems s Yeast mating factors Epinephrines other hormones and neurotransmitters Extremely widespread functions Embryonic develop Sensory 60% of medicines used today modify G- pathway tyrosine kinases (RTKs) are s that attach phosphates to tyrosines A tyrosine kinase can trigger multiple signal transduction pathways at once Abnormal functioning of RTKs is associated with many types of cancers such as breast cancer Figure.7c (ligand) α helix in the osines CYTOLASM Ligand-binding site tyrosine kinase s (inactive monomers) Activated relay s Dimer A ligand-gated ion channel acts as a gate when the changes shape When a signal binds as a ligand to the, the gate allows specific ions, such as Na + or, through a channel in the Ligand-gated ion channels play important roles in the nerve system. 6 AT 6 AD Activated tyrosine Fully activated kinase regions tyrosine (unphosphorylated kinase dimer) (phosphorylated dimer) 4 relay s Cellular response Cellular response 4
Figure.7d Intracellular s (ligand) Gate closed Ions lasma Ligand-gated ion channel Gate open Cellular response Gate closed 5 Intracellular s are found in the cytosol or nucleus of target cells Small or hydrophobic chemical messengers can readily cross the and activate s Examples of hydrophobic messengers are the steroid and thyroid hormones of animals An activated hormone- complex can act as a transcription factor, turning on specific genes 6 Figure.9- Hormone (testosterone) Figure.9- Hormone (testosterone) lasma lasma Hormone complex CYTOLASM 7 CYTOLASM 8 Figure.9- Hormone (testosterone) Figure.9-4 Hormone (testosterone) lasma Hormone complex lasma Hormone complex mrna CYTOLASM 9 CYTOLASM 0
Figure.9-5 Hormone (testosterone) mrna lasma Hormone complex New Concept.: Transduction: Cascades of molecular interactions relay signals from s to target s in the cell Signal transduction usually involves multiple steps Multistep pathways can amplify a signal: A few s can produce a large cellular response Multistep pathways provide more opportunities for coordination and regulation of the cellular response CYTOLASM Signal Transduction athways The s that relay a signal from to response are mostly s Like falling dominoes, the activates another, which activates another, and so on, until the producing the response is activated At each step, the signal is transduced into a different form, usually a shape change in a rotein hosphorylation and Dephosphorylation In many pathways, the signal is transmitted by a cascade of phosphorylations rotein kinases transfer phosphates from AT to, a process called phosphorylation 4 Figure.0 rotein phosphatases remove the phosphates from s, 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 kinase Activated relay kinase kinase i AT AD kinase hosphorylation cascade kinase AT AD i kinase 5 AT i AD Cellular response 6
Small Molecules and Ions as Second Messengers The extracellular signal (ligand) that binds to the is a pathway s first messenger Second messengers are small, non, watersoluble s or ions that spread throughout a cell by diffusion Second messengers participate in pathways initiated by GCRs and RTKs Cyclic AM and calcium ions are common second messengers 7 Cyclic AM Cyclic AM (cam) is one of the most widely used second messengers Adenylyl cyclase, an enzyme in the plasma, converts AT to cam in response to an extracellular signal Figure. 8 Many signal s trigger formation of cam Other components of cam pathways are G s, G -coupled s, and kinases cam usually activates kinase A, which phosphorylates various other s Further regulation of cell metabolism is provided by G- systems that inhibit adenylyl cyclase Figure. G -coupled First messenger (signaling such as epinephrine) G GT AT cam Adenylyl cyclase Second messenger rotein kinase A 9 Cellular responses 40 Calcium Ions Calcium ions ( ) act as a second messenger in many pathways Calcium is an important second messenger because cells can regulate its concentration Functions Muscle contraction, secretion and cell division in animal cells Greening response to light in plants Figure. CYTOSOL AT AT pump Mitochondrion Nucleus pump lasma pump Endoplasmic reticulum (ER) 4 Key High [Ca + ] Low [Ca + ] 4
Figure.4- Inositol Triphosphate (I ) and Diacylglycerol (DAG) EXTRA- CELLULAR (first messenger) G DAG A signal relayed by a signal transduction pathway may trigger an increase in calcium in the cytosol athways leading to the release of calcium involve inositol triphosphate (I ) and diacylglycerol (DAG) as additional second messengers G -coupled GT I -gated calcium channel hospholipase C I I (second messenger) Endoplasmic reticulum (ER) 4 CYTOSOL 44 Figure.4- Figure.4- EXTRA- CELLULAR (first messenger) EXTRA- CELLULAR (first messenger) G G DAG DAG G -coupled GT hospholipase C I G -coupled GT hospholipase C I I (second messenger) I (second messenger) I -gated calcium channel I -gated calcium channel Endoplasmic reticulum (ER) CYTOSOL (second messenger) 45 Endoplasmic reticulum (ER) CYTOSOL (second messenger) Various s activated Cellular responses 46 Concept.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 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 s, usually by turning genes on or off in the nucleus The final activated in the signaling pathway may function as a transcription factor 47 48
Figure.5 Growth factor hosphorylation cascade Reception Transduction Other pathways regulate the activity of enzymes rather than their synthesis CYTOLASM transcription factor transcription factor Response Figure.6 Gene mrna 49 50 Figure.7 RESULTS pathways can also affect the overall behavior of a cell, for example, changes in cell shape CONCLUSION Mating factor activates. Wild type (with shmoos) Fus formin Mating factor G -coupled Shmoo projection forming Formin 5 GD Fus Actin GT subunit G binds GT and becomes activated. hosphorylation Formin Formin cascade 4 Fus phosphorylates Fus Fus formin, Microfilament activating it. hosphorylation cascade 5 Formin initiates growth of microfilaments that form activates Fus, which moves the shmoo projections. to plasma. 5 Fine-Tuning of the Response There are four aspects of fine-tuning to consider Amplifying the signal (and thus the response) Specificity of the response Overall efficiency of response, enhanced by scaffolding s Termination of the signal 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 5 54
The Specificity of Cell and Coordination of the Response Different kinds of cells have different collections of s These different s allow cells to detect and respond to different signals Even the same signal can have different effects in cells with different s and pathways athway branching and cross-talk further help the cell coordinate incoming signals 55 Figure.8a Response Cell A. athway leads to a single response. Relay s Response Response Cell B. athway branches, leading to two responses. 56 Figure.8b Efficiency: Scaffolding roteins and Complexes Activation or inhibition Response 4 Response 5 Scaffolding s are large relay s to which other relay s are attached Scaffolding s can increase the signal transduction efficiency by grouping together different s involved in the same pathway In some cases, scaffolding s may also help activate some of the relay s Cell C. Cross-talk occurs between two pathways. Cell D. Different leads to a different response. 57 58 Figure.9 Scaffolding lasma Three different kinases Termination of the Signal Inactivation mechanisms are an essential aspect of cell signaling If ligand concentration falls, fewer s will be bound Unbound s revert to an inactive state 59 60
Concept.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 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 s that accelerate apoptosis override those that put the brakes on apoptosis 6 6 Figure.a Ced-9 (active) inhibits Ced-4 activity Mitochondrion Figure.b Deathsignaling Ced-9 (inactive) Cell forms blebs Ced-4 Ced- Other proteases for deathsignaling Ced-4 Ced- s Activation cascade Nucleases (a) No death signal 6 (b) Death signal 64 Apoptotic athways and the Signals That Trigger Them Caspases are the main proteases (enzymes that cut up s) that carry out apoptosis Apoptosis can be triggered by An extracellular death-signaling ligand damage in the nucleus rotein misfolding in the endoplasmic reticulum 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, arkinson s and Alzheimer s); interference with apoptosis may contribute to some cancers 65 66