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Overview: The Cellular Internet
Cell-to-cell communication is essential for multicellular organisms Biologists have discovered some universal mechanisms of cellular regulation
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1. Evolution of Cell Signaling
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
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2. Yeast mating Exchange of mating factors a factor Receptor a a
Yeast cell, mating type a Yeast cell, mating type a Mating a a New a/a cell a/a
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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
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LE 11-3 Plasma membranes Gap junctions between animal cells Plasmodesmata between plant cells Cell junctions Cell-cell recognition
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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
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3. Paracrine signaling (e. g. growth factors) Synaptic signaling (e. g
3. Paracrine signaling (e.g. growth factors) Synaptic signaling (e.g. neurotransmitters) Hormonal signaling (long distance) Local signaling Long-distance signaling Target cell Electrical signal along nerve cell triggers release of neurotransmitter Endocrine cell Blood vessel Neurotransmitter diffuses across synapse Secreting cell Secretory vesicle Hormone travels in bloodstream to target cells Local regulator diffuses through extracellular fluid Target cell is stimulated Target cell Paracrine signaling Synaptic signaling Hormonal signaling
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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
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4. Reception EXTRACELLULAR FLUID CYTOPLASM Plasma membrane Reception
Transduction Receptor Signal molecule
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Relay molecules in a signal transduction
EXTRACELLULAR FLUID CYTOPLASM Plasma membrane Reception Transduction Receptor Relay molecules in a signal transduction pathway Signal molecule
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Relay molecules in a signal transduction
4. Response EXTRACELLULAR FLUID CYTOPLASM Plasma membrane Reception Transduction Response Receptor Activation of cellular response Relay molecules in a signal transduction pathway Signal molecule
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6. 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 The binding of the ligand causes a conformational change in the receptor Most signal receptors are plasma membrane proteins
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7. 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
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7. 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
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7-10. (See book!) First messenger (signal molecule
such as epinephrine) Adenylyl cyclase G protein G-protein-linked receptor GTP ATP Second messenger cAMP Protein kinase A Cellular responses
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11 & 12. Many different signaling molecules use G-protein-linked receptors—yeast mating factors, epinephrine and many other hormones, and neurotransmitters. Once the G-protein-linked receptor is activated, the G protein is activated by GTP. The G protein also functions as a GTPase and soon hydrolyzes its bound GTP to GDP. G protein is now inactive again, and can be reused.
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13. Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines A receptor tyrosine kinase can trigger multiple signal transduction pathways at once
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14, 15. Kinases are enzymes that transfer phophate groups. The part of the receptor protein that extends out into the cytoplasm is a tyrosine kinase—it transfers a phosphate group from ATP to tyrosine. One receptor tyrosine kinase complex may activate ten or more different transduction pathways, G-protein-linked receptors can’t do this.
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16—19. Signal molecule Signal-binding site a Helix in the membrane
Tyrosines Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Receptor tyrosine kinase proteins (inactive monomers) Dimer CYTOPLASM Activated relay proteins Cellular response 1 Tyr Tyr P Tyr P Tyr P Tyr Tyr P Tyr Tyr P Tyr Tyr P P P Tyr Tyr Tyr Tyr P Tyr Tyr P P Tyr Tyr P Cellular response 2 6 ATP 6 ADP Activated tyrosine- kinase regions (unphosphorylated dimer) Fully activated receptor tyrosine-kinase (phosphorylated dimer) Inactive relay proteins
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20. Each activated protein in the figure triggers a signal ____________________ pathway leading to a _________________ response.
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An ion channel receptor acts as a gate when the receptor changes shape
21. 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
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21—23. Signal molecule (ligand) Gate closed Ions Plasma membrane
Ligand-gated ion channel receptor Gate open Cellular response Gate closed
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24. Ligand-gated ion channels and voltage-gated ion channels are important to the ________________ system.
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25. 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
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26. Hormone EXTRACELLULAR (testosterone) FLUID The steroid
hormone testosterone passes through the plasma membrane. Plasma membrane Testosterone binds to a receptor protein in the cytoplasm, activating it. Receptor protein Hormone- receptor complex The hormone- receptor complex enters the nucleus and binds to specific genes. DNA mRNA The bound protein stimulates the transcription of the gene into mRNA. NUCLEUS New protein The mRNA is translated into a specific protein. CYTOPLASM
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27 Transcription factors control which genes are turned on in a particular cell at a particular time. They do this by controlling transcription of DNA to mRNA.
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Transduction usually involves multiple steps
28. 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
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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
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29. Protein Phosphorylation and Dephosphorylation
In many pathways, the signal is transmitted by a cascade of protein phosphorylations Protein kinases transfer phosphate groups from ATP Protein phosphatase enzymes remove the phosphates This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off
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30. Signal molecule Receptor Activated relay molecule Inactive
protein kinase 1 Active protein kinase 1 Inactive protein kinase 2 ATP ADP Active protein kinase 2 P Phosphorylation cascade PP P i Inactive protein kinase 3 ATP ADP Active protein kinase 3 P PP P i Inactive protein ATP ADP P Active protein Cellular response PP P i
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31. 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
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32. 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
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32. Pyrophosphate ATP Cyclic AMP AMP Adenylyl cyclase
Phosphodiesterase Pyrophosphate H2O P P i ATP Cyclic AMP AMP
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Many signal molecules trigger formation of cAMP
33-34. 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
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31—35. First messenger (signal molecule such as epinephrine) Adenylyl
cyclase G protein G-protein-linked receptor GTP ATP Second messenger cAMP Protein kinase A Cellular responses
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35. Cholera Caused by bacterium Vibrio cholerae, found in contaminated drinking water Bacteria secrete a toxin which modifies a G protein involved in regulating salt and water secretion G protein is “stuck” in its active form, continuously stimulating adenylyl cyclase to make cAMP, which causes intestinal cells to secrete large amounts of water and salts into intestine This causes profuse, and often deadly, diarrhea.
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36. Calcium ions and Inositol Triphosphate (IP3)
Calcium ions (Ca2+) act as a second messenger in many pathways Neurotransmitters, growth factors, and some hormones use Ca2+ as a second messenger Calcium is an important second messenger because cells can regulate its concentration
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37. 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
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37. EXTRACELLULAR FLUID Plasma membrane Ca2+ pump ATP Mitochondrion
Nucleus CYTOSOL Ca2+ pump Endoplasmic reticulum (ER) ATP Ca2+ pump Key High [Ca2+] Low [Ca2+]
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EXTRACELLULAR Signal molecule FLUID (first messenger) G protein DAG
37. EXTRACELLULAR FLUID Signal molecule (first messenger) G protein DAG GTP G-protein-linked receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Endoplasmic reticulum (ER) Ca2+ CYTOSOL
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EXTRACELLULAR Signal molecule FLUID (first messenger) G protein DAG
37. EXTRACELLULAR FLUID Signal molecule (first messenger) G protein DAG GTP G-protein-linked receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Endoplasmic reticulum (ER) Ca2+ Ca2+ (second messenger) CYTOSOL
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EXTRACELLULAR Signal molecule FLUID (first messenger) G protein DAG
37. EXTRACELLULAR FLUID Signal molecule (first messenger) G protein DAG GTP G-protein-linked receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Cellular re- sponses Various proteins activated Endoplasmic reticulum (ER) Ca2+ Ca2+ (second messenger) CYTOSOL
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38. 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
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The final activated molecule may function as a transcription factor
38. 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
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38. Growth factor Reception Receptor Phosphorylation cascade
Transduction CYTOPLASM Inactive transcription factor Active transcription factor Response P DNA Gene NUCLEUS mRNA
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39. Responses in the cytoplasm usually involve activation of certain enzymes i.e. the response to epinephrine is the activation of glycogen phosphorylase
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40. Reception Binding of epinephrine to G-protein-linked 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)
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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
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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
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41. 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
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41. Signal molecule Receptor Relay molecules Response 1 Response 2
Cell A. Pathway leads to a single response Cell B. Pathway branches, leading to two responses Activation or inhibition Response 4 Response 5 Cell C. Cross-talk occurs between two pathways Cell D. Different receptor leads to a different response
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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
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Signal Plasma molecule membrane Receptor Three different protein
42. Signal molecule Plasma membrane Receptor Three different protein kinases Scaffolding protein
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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
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Apoptosis Apoptosis is programmed cell death. Newly formed enzymes break down many chemical components of the cell, such as DNA, RNA, proteins, and membrane lipids. In plants, ethylene causes programmed destruction of cells, organs, or the whole plant. (e.g. plants that shed leaves in autumn) Once natural killer cells attach to a virus-infected cell or a cancer cell, it releases chemicals that lead to apoptosis
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