Ch9_Cellular Signaling.pdf

Chapter 9-Cellular Signaling Pei-Feng Liu (劉佩芬) Department of Biomedical Science and Environmental Biology (生物醫學暨環境生物學系) Kaohsiung Medical University (KMU) [email protected]...

Chapter 9-Cellular Signaling Pei-Feng Liu (劉佩芬) Department of Biomedical Science and Environmental Biology (生物醫學暨環境生物學系) Kaohsiung Medical University (KMU) [email protected] 第一教學大樓N916 1 © 2021 Pearson Education Ltd.  Outline 9-1: External signals are converted to responses within the cell 9-2: Reception: A signaling molecule binds to a receptor protein, causing it to change shape (four main types of receptors) 9-3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell 9-4: Response: Cell signaling leads to regulation of transcription or cytoplasmic activities 9-5: Apoptosis requires integration of multiple cell-signaling pathways 2 © 2021 Pearson Education Ltd.  3 © 2021 Pearson Education Ltd. 9.1: External signals are converted to responses within the cell ▪ Cells can signal to each other and interpret the signals they receive from other cells and the environment ▪ Signals are most often chemicals ▪ The same small set of cell- Epinephrine (adrenaline) signaling mechanisms shows up in diverse species and processes ▪ Communication among microorganisms provides some insight into how cells send, receive, and respond to signals 4 © 2021 Pearson Education Ltd. 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 ▪ The binding of a mating factor at the cell surface initiates a series of steps called a signal transduction pathway ▪ Molecular details of signal transduction in yeasts and mammals are very similar. 5 © 2021 Pearson Education Ltd.  ▪ Ancestral signaling molecules likely evolved in prokaryotes and single-celled eukaryotes and were adopted for use in their multicellular descendants ▪ Cell signaling is critical among prokaryotes ▪ A concentration of signaling molecules allows bacteria to sense local population density in a process called quorum sensing ▪ An example of quorum sensing is the formation of a biofilm 6 © 2021 Pearson Education Ltd.  ▪ A biofilm is an aggregation of bacterial cells adhered to a surface ▪ Another example of medical importance is the secretion of toxins by infectious bacteria (ex. Staphylococcus aureus) ▪ Interfering with the signaling pathways used in quorum sensing may be a promising approach as an alternative to antibiotic treatment 7 © 2021 Pearson Education Ltd. Long-Distance and Local Signaling ▪ In long-distance signaling, plants and animals use chemicals called hormones ▪ Hormonal signaling in animals is called endocrine signaling; specialized cells release hormones, which travel to target cells via the circulatory system ▪ The ability of a cell to respond to a signal depends on whether or not it has a receptor specific to that signal 8 © 2021 Pearson Education Ltd.  ▪ In other cases, animal cells communicate using secreted messenger molecules that travel only short distances ▪ Growth factors, which stimulate nearby target cells to grow and divide, are one class of such local regulators in animals ▪ This type of local signaling in animals is called paracrine signaling 9 © 2021 Pearson Education Ltd.  ▪ Synaptic signaling occurs in the animal nervous system when a neurotransmitter is released in response to an electric signal 10 © 2021 Pearson Education Ltd. The Three Stages of Cell Signaling: A Preview ▪ Earl W. Sutherland and colleagues discovered how the hormone epinephrine acts on cells ▪ Sutherland suggested that cells receiving signals went through three processes ▪ Reception ▪ Transduction ▪ Response 11 © 2021 Pearson Education Ltd. ▪ In reception, the target cell detects a signaling molecule that binds to a receptor protein on the cell surface ▪ In transduction, the binding of the signaling molecule alters the receptor and initiates a signal transduction pathway; transduction often occurs in a series of steps ▪ In response, the transduced signal triggers a specific response in the target cell 12 © 2021 Pearson Education Ltd. Animation: Overview of Cell Signaling 13 © 2021 Pearson Education Ltd. 9.2: 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 14 © 2021 Pearson Education Ltd. Receptors in the Plasma Membrane ▪ G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors ▪ 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 - ligand-gated ion channel 15 © 2021 Pearson Education Ltd.  (1) G protein-coupled receptors ▪ G protein-coupled receptors (GPCRs) are cell-surface transmembrane receptors that work with the help of a G protein ▪ G proteins bind the energy-rich GTP ▪ G proteins are all very similar in structure ▪ GPCR systems are extremely widespread and diverse in their functions 16 © 2021 Pearson Education Ltd. Figure 9.8b 17 © 2021 Pearson Education Ltd.  (2) Receptor tyrosine kinases ▪ Receptor tyrosine kinases (RTKs) are membrane receptors that transfer phosphate groups from ATP to another protein ▪ A receptor tyrosine kinase can trigger multiple signal transduction pathways at once ▪ Abnormal functioning of RTKs is associated with many types of cancers 18 © 2021 Pearson Education Ltd. Figure 9.8c 19 © 2021 Pearson Education Ltd.  (3) ligand-gated ion channel ▪ A ligand-gated ion channel receptor acts as a gate that opens and closes 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 20 © 2021 Pearson Education Ltd. Intracellular Receptors ▪ Intracellular receptor proteins are found in the cytoplasm 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 or off specific genes 21 © 2021 Pearson Education Ltd. 9.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell ▪ Cell signaling is usually a multistep process ▪ Multistep pathways can greatly amplify a signal ▪ Multistep pathways provide more opportunities for coordination and regulation of the cellular response 22 © 2021 Pearson Education Ltd. Signal Transduction Pathways ▪ The binding of a signaling molecule to a receptor triggers the first step in a chain of molecular interactions ▪ 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 23 © 2021 Pearson Education Ltd.  Protein Phosphorylation and Dephosphorylation ▪ Phosphorylation and dephosphorylation of proteins is a widespread cellular mechanism for regulating protein activity ▪ Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation ▪ Many relay molecules in signal transduction pathways are protein kinases, creating a phosphorylation cascade 24 © 2021 Pearson Education Ltd. ▪ Protein phosphatases rapidly 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 25 © 2021 Pearson Education Ltd. Small Molecules and Ions as Second Messengers ▪ Many signaling pathways involve second messengers ▪ These 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 26 © 2021 Pearson Education Ltd. 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 5′C P P P Adenylyl cyclase Phosphodiesterase P P Pyrophosphate 3′C H2O ATP P Pi cAMP AMP 27 © 2021 Pearson Education Ltd. ▪ 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 ▪ The cholera bacterium, Vibrio cholerae, produces a toxin that modifies a G protein so that it is stuck in its active form 28 © 2021 Pearson Education Ltd. ▪ Understanding of the role of cAMP in G protein signaling pathways helps explain how certain microbes cause disease ▪ This protein continually makes cAMP, causing intestinal cells to secrete large amounts of salt into the intestines ▪ Water follows by osmosis, and an untreated person can soon die from loss of water and salt 29 © 2021 Pearson Education Ltd. Calcium Ions and Inositol Triphosphate (IP3) ▪ Calcium ions (Ca2+) are used widely as a second messenger ▪ Ca2+ can function as a second messenger because its concentration in the cytosol is normally much lower than the concentration outside the cell ▪ A small change in number of calcium ions thus represents a relatively large percentage change in calcium concentration 30 © 2021 Pearson Education Ltd. ▪ 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 ▪ These two are produced by cleavage of a certain phospholipid in the plasma membrane 31 © 2021 Pearson Education Ltd. Animation: Signal Transduction Pathways 32 © 2021 Pearson Education Ltd.  9.4: Response: Cell signaling leads to regulation of transcription or cytoplasmic activities Nuclear and Cytoplasmic Responses ▪ Ultimately, a signal transduction pathway leads to regulation of one or more cellular activities ▪ The response may occur in the nucleus or in the cytoplasm ▪ 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 © 2021 Pearson Education Ltd. 33 Regulation of the Response ▪ A response to a signal may not be simply “on” or “off” ▪ There are four aspects of signal regulation: - Amplification of the signal (and thus the response) - Specificity of the response - Overall efficiency of response, enhanced by scaffolding proteins - Termination of the signal 34 © 2021 Pearson Education Ltd. (1) Signal Amplification ▪ Enzyme cascades amplify the cell’s response to the signal ▪ At each step, the number of activated products can be much greater than in the preceding step © 2021 Pearson Education Ltd. 35 (2) The Specificity of Cell Signaling and Coordination of the Response (a) Different kinds of cells have different collections of proteins (a) The same signal can have different effects in cells with different proteins and pathways (b) These different proteins allow cells to detect and respond to different signals (c) Pathway branching and “cross-talk” further help the cell coordinate incoming signals (a) (b) (c) (a) © 2021 Pearson Education Ltd. 36 (3) 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 37 © 2021 Pearson Education Ltd. (4) Termination of the Signal ▪ Inactivation mechanisms are an essential aspect of cell signaling ▪ If the concentration of external signaling molecules falls, fewer receptors will be bound ▪ Unbound receptors revert to an inactive state 38 © 2021 Pearson Education Ltd. 9.5: Apoptosis requires integration of multiple cell- signaling pathways ▪ Cells that are infected, damaged, or at the end of their functional lives often undergo “programmed cell death” ▪ Apoptosis is the best-understood type ▪ 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 39 © 2021 Pearson Education Ltd. ▪ Apoptosis evolved early in animal evolution and is essential for the development and maintenance of all animals ▪ For example, apoptosis is a normal part of development of hands and feet in humans (and paws in other mammals) ▪ Apoptosis may be involved in some diseases (for example, Parkinson’s and Alzheimer’s); interference with apoptosis may contribute to some cancers 40 © 2021 Pearson Education Ltd. Apoptosis in the Soil Worm Caenorhabditis elegans ▪ In worms and other organisms, apoptosis is triggered by signals that activate a cascade of “suicide” proteins in the cells programmed to die ▪ When the death signal is received, an apoptosis-inhibiting protein (Ced-9) is inactivated, triggering a cascade of caspase proteins that promote apoptosis ▪ The chief caspase in the nematode is called Ced-3 41 © 2021 Pearson Education Ltd. Apoptotic Pathways and the Signals That Trigger Them ▪ In humans and other mammals, several different pathways, including about 15 caspases, can carry out apoptosis ▪ Apoptosis can be triggered by signals from outside the cell or inside it ▪ Internal signals can result from irreparable DNA damage or excessive protein misfolding 42 © 2021 Pearson Education Ltd.  43 © 2021 Pearson Education Ltd.  44 © 2021 Pearson Education Ltd. Annu. Rev. Biochem. 2004. 73:87–106  Summary ▪ Examples of long-distance and local signaling ▪ Three stages of cell signaling - types of receptors in the plasma membrane - types of signaling molecules - aspects of signal regulation ▪ Apoptotic pathways 45 © 2021 Pearson Education Ltd.