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Signal transduction ....................
- 1. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Overview: The Cellular Internet • Cell-to-cell communication is essential for multicellular organisms • Biologists have discovered some universal mechanisms of cellular regulation
- 2. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Concept 11.1: External signals are converted into responses within the cell • Microbes are a window on the role of cell signaling in the evolution of life
- 3. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Evolution of Cell Signaling • 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 • Pathway similarities suggest that ancestral signaling molecules evolved in prokaryotes and have since been adopted by eukaryotes
- 4. LE 11-2 Exchange of mating factors Mating Receptor a a a factor a a a factor Yeast cell, mating type a Yeast cell, mating type a a/a New a/a cell
- 5. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Local and Long-Distance Signaling • Cells in a multicellular organisms 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
- 6. LE 11-3 Plasma membranes Gap junctions between animal cells Cell junctions Cell-cell recognition Plasmodesmata between plant cells
- 7. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • 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
- 8. LE 11-4 Paracrine signaling Local regulator diffuses through extracellular fluid Secretory vesicle Secreting cell Target cell Local signaling Electrical signal along nerve cell triggers release of neurotransmitter Neurotransmitter diffuses across synapse Endocrine cell Blood vessel Long-distance signaling Hormone travels in bloodstream to target cells Synaptic signaling Target cell is stimulated Hormonal signaling Target cell
- 9. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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
- 11. LE 11-5_2 EXTRACELLULAR FLUID Reception Plasma membrane Transduction CYTOPLASM Receptor Signal molecule Relay molecules in a signal transduction pathway
- 12. LE 11-5_3 EXTRACELLULAR FLUID Reception Plasma membrane Transduction CYTOPLASM Receptor Signal molecule Relay molecules in a signal transduction pathway Response Activation of cellular response
- 13. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Concept 11.2: Reception: A signal molecule binds to a receptor protein, causing it to change shape • The binding between a signal molecule (ligand) and receptor is highly specific • A conformational change in a receptor is often the initial transduction of the signal • Most signal receptors are plasma membrane proteins
- 14. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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
- 15. LE 11-6 EXTRACELLULAR FLUID Plasma membrane The steroid hormone testosterone passes through the plasma membrane. Testosterone binds to a receptor protein in the cytoplasm, activating it. The hormone- receptor complex enters the nucleus and binds to specific genes. The bound protein stimulates the transcription of the gene into mRNA. The mRNA is translated into a specific protein. CYTOPLASM NUCLEUS DNA Hormone (testosterone) Receptor protein Hormone- receptor complex mRNA New protein
- 16. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Receptors in the Plasma Membrane • 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-linked receptors – Receptor tyrosine kinases – Ion channel receptors
- 17. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • A G-protein-linked 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
- 18. LE 11-7aa Segment that interacts with G proteins Signal-binding site G-protein-linked receptor
- 19. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines • A receptor tyrosine kinase can trigger multiple signal transduction pathways at once
- 20. LE 11-7b Signal molecule a Helix in the membrane Signal-binding site Tyr Tyr Tyr Tyr Tyr Tyr Tyrosines Receptor tyrosine kinase proteins (inactive monomers) CYTOPLASM Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Activated tyrosine- kinase regions (unphosphorylated dimer) Signal molecule Dimer Fully activated receptor tyrosine-kinase (phosphorylated dimer) Tyr Tyr Tyr Tyr Tyr Tyr P P P P P P ATP 6 ADP Tyr Tyr Tyr Tyr Tyr Tyr P P P P P P Inactive relay proteins Cellular response 2 Cellular response 1 Activated relay proteins 6
- 21. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • An 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
- 22. LE 11-7c Signal molecule (ligand) Gate closed Ions Ligand-gated ion channel receptor Plasma membrane Gate closed Gate open Cellular response
- 23. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Concept 11.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell • 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
- 24. Copyright © 2005 Pearson Education, Inc. publishing as 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 conformational change
- 25. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Protein Phosphorylation and Dephosphorylation • In many pathways, the signal is transmitted by a cascade of protein phosphorylations • Phosphatase enzymes remove the phosphates • This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off
- 26. LE 11-8 Signal molecule Activated relay molecule Receptor Inactive protein kinase 1 Active protein kinase 1 Inactive protein kinase 2 Active protein kinase 2 Inactive protein kinase 3 Active protein kinase 3 ADP Inactive protein Active protein Cellular response ATP PP Pi ADP ATP PP Pi ADP ATP PP Pi P P P
- 27. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Small Molecules and Ions as Second Messengers • Second messengers are small, nonprotein, water- soluble molecules or ions • The extracellular signal molecule that binds to the membrane is a pathway’s “first messenger” • Second messengers can readily spread throughout cells by diffusion • Second messengers participate in pathways initiated by G-protein-linked receptors and receptor tyrosine kinases
- 28. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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
- 29. LE 11-9 ATP Cyclic AMP AMP Adenylyl cyclase Pyrophosphate P P i Phosphodiesterase H2O
- 30. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Many signal molecules trigger formation of cAMP • Other components of cAMP pathways are G proteins, G-protein-linked 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
- 31. LE 11-10 cAMP ATP Second messenger First messenger (signal molecule such as epinephrine) G-protein-linked receptor G protein Adenylyl cyclase Protein kinase A Cellular responses GTP
- 32. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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
- 33. LE 11-11 ATP EXTRACELLULAR FLUID ATP Mitochondrion Ca2+ pump Plasma membrane CYTOSOL Endoplasmic reticulum (ER) Ca2+ pump Ca2+ pump High [Ca2+] Key Nucleus Low [Ca2+]
- 34. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • 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 second messengers Animation: Signal Transduction Pathways
- 35. LE 11-12_1 CYTOSOL Ca2+ Endoplasmic reticulum (ER) IP3-gated calcium channel IP3 (second messenger) DAG PIP2 G-protein-linked receptor Phospholipase C G protein Signal molecule (first messenger) EXTRACELLULAR FLUID GTP
- 36. LE 11-12_2 CYTOSOL Ca2+ Endoplasmic reticulum (ER) IP3-gated calcium channel IP3 (second messenger) DAG PIP2 G-protein-linked receptor Phospholipase C G protein Signal molecule (first messenger) EXTRACELLULAR FLUID GTP Ca2+ (second messenger)
- 37. LE 11-12_3 CYTOSOL Ca2+ Endoplasmic reticulum (ER) IP3-gated calcium channel IP3 (second messenger) DAG PIP2 G-protein-linked receptor Phospholipase C G protein Signal molecule (first messenger) EXTRACELLULAR FLUID GTP Ca2+ (second messenger) Various proteins activated Cellular re- sponses
- 38. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Concept 11.4: Response: Cell signaling leads to regulation of cytoplasmic activities or transcription • The cell’s response to an extracellular signal is sometimes called the “output response”
- 39. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Cytoplasmic and Nuclear Responses • 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 pathways regulate the activity of enzymes
- 40. LE 11-13 Binding of epinephrine to G-protein-linked receptor (1 molecule) Reception Transduction Inactive G protein Active G protein (102 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (102) ATP Cyclic AMP (104) Inactive protein kinase A Inactive phosphorylase kinase Active protein kinase A (104) Active phosphorylase kinase (105) Active glycogen phosphorylase (106) Inactive glycogen phosphorylase Glycogen Response Glucose-1-phosphate (108 molecules)
- 41. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Many other 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
- 43. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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
- 44. Copyright © 2005 Pearson Education, Inc. publishing as 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
- 45. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The Specificity of Cell Signaling • Different kinds of cells have different collections of proteins • These differences in proteins give each kind of cell specificity in detecting and responding to signals • The response of a cell to a signal depends on the cell’s particular collection of proteins • Pathway branching and “cross-talk” further help the cell coordinate incoming signals
- 46. LE 11-15 Signal molecule Receptor Relay molecules Response 1 Response 2 Response 3 Cell B. Pathway branches, leading to two responses Cell A. Pathway leads to a single response Cell C. Cross-talk occurs between two pathways Response 4 Response 5 Activation or inhibition Cell D. Different receptor leads to a different response
- 47. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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
- 49. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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