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Cell Communication. Evolution of Cell Signaling A signal-transduction pathway is a series of steps by which a signal on a cell’s surface is converted.

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Presentation on theme: "Cell Communication. Evolution of Cell Signaling A signal-transduction pathway is a series of steps by which a signal on a cell’s surface is converted."— Presentation transcript:

1 Cell Communication

2 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 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 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 Pathway similarities suggest that ancestral signaling molecules evolved in prokaryotes and have since been adopted by eukaryotes

3 Communication Between Mating Yeast Cells Communication Between Mating Yeast Cells  factor Receptor Exchange of mating factors. Each cell type secretes a mating factor that binds to receptors on the other cell type. Mating. Binding of the factors to receptors induces changes in the cells that lead to their fusion. New a/  cell. The nucleus of the fused cell includes all the genes from the a and  cells.  factor Yeast cell, mating type a Yeast cell, mating type    a/  a a 1 3 2

4 Cells Communication Direct contact Direct contact Paracrine signaling Paracrine signaling Endocrine signaling Endocrine signaling Synaptic signaling Synaptic signaling

5 Direct Contact Cells touch each other and signal molecules travel through special connections called communicating junctions Cells touch each other and signal molecules travel through special connections called communicating junctions Communicating junctions link the cytoplasms of 2 cells together, permitting the controlled passage of small molecules or ions between them. Communicating junctions link the cytoplasms of 2 cells together, permitting the controlled passage of small molecules or ions between them. Plasma membranes Gap junctions between animal cells Cell junctions Cell-cell recognition Plasmodesmata between plant cells

6 (a) Paracrine signaling. A secreting cell acts on nearby target cells by discharging molecules of a local regulator (a growth factor, for example) into the extracellular fluid. (b) Synaptic signaling. A nerve cell releases neurotransmitter molecules into a synapse, stimulating the target cell. Hormone travels in bloodstream to target cells (c) Hormonal signaling. Specialized endocrine cells secrete hormones into body fluids, often the blood. Hormones may reach virtually all body cells. Local regulator diffuses through extracellular fluid Secreting cell Target cell Secretory vesicle Electrical signal along nerve cell triggers release of neurotransmitter Neurotransmitter diffuses across synapse Target cell is stimulated Local signalingLong-distance signaling Endocrine cell Blood vessel Target cell Cell Communication In Animals In many other cases, animal cells communicate using local regulators, messenger molecules that travel only short distances 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 In long-distance signaling, plants and animals use chemicals called hormones

7 Cell Signaling EXTRACELLULAR FLUID Receptor Signal molecule Relay molecules in a signal transduction pathway Plasma membrane CYTOPLASM Activation of cellular response ReceptionTransductionResponse 123 The cells of a organism communicate with each other by releasing signal molecules that bind to receptor proteins located either on or inside of target cells. The cells of a organism communicate with each other by releasing signal molecules that bind to receptor proteins located either on or inside of target cells. Three stages of cell signaling: Three stages of cell signaling: Reception - each target cell has receptors that detect a specific signal molecule and binds to it Reception - each target cell has receptors that detect a specific signal molecule and binds to it Transduction – binding of the signal molecule changes the receptor protein in some way that initiates transduction or conversion of the signal to a form that can bring about a specific cellular response Transduction – binding of the signal molecule changes the receptor protein in some way that initiates transduction or conversion of the signal to a form that can bring about a specific cellular response Response – transduced signal triggers a specific cellular response, any cell activity Response – transduced signal triggers a specific cellular response, any cell activity

8 Reception A signal molecule binds to a receptor protein, causing it to change shape A signal molecule binds to a receptor protein, causing it to change shape The binding between signal molecule (ligand) and receptor is highly specific The binding between signal molecule (ligand) and receptor is highly specific A conformational change in a receptor A conformational change in a receptor Is often the initial transduction of the signal Is often the initial transduction of the signal

9 Receptors Intracellular receptors Intracellular receptors Some signal molecules that are small or hydrophobic can pass through the plasma membrane and bind to receptors located inside the cell Some signal molecules that are small or hydrophobic can pass through the plasma membrane and bind to receptors located inside the cell Intracellular receptors are cytoplasmic or nuclear proteins Intracellular receptors are cytoplasmic or nuclear proteins Cell surface receptors. - Signal molecules that cannot pass through the plasma membrane bind to receptors located on the surface of the membrane Cell surface receptors. - Signal molecules that cannot pass through the plasma membrane bind to receptors located on the surface of the membrane

10 Intracellular Receptors Gene Regulators Gene Regulators Signal molecule joins to the receptor, the receptor changes shape and a DNA binding site is exposed. Signal molecule joins to the receptor, the receptor changes shape and a DNA binding site is exposed. The DNA binding site joins to a specific segment of DNA and activates (or suppresses) a particular gene The DNA binding site joins to a specific segment of DNA and activates (or suppresses) a particular gene Enzyme Receptor Enzyme Receptor These receptors function as enzymes – proteins that catalyze (speed up) specific chemical reactions. These receptors function as enzymes – proteins that catalyze (speed up) specific chemical reactions. When a signal molecule joins to the receptor, the receptor’s catalytic domain is activated (or deactivated). When a signal molecule joins to the receptor, the receptor’s catalytic domain is activated (or deactivated).

11 Hormone (testosterone) EXTRACELLULAR FLUID Receptor protein Plasma membrane Hormone- receptor complex DNA mRNA NUCLEUS CYTOPLASM New protein The steroid hormone testosterone passes through the plasma membrane. 1 Testosterone binds to a receptor protein in the cytoplasm, activating it. 2 The hormone- receptor complex enters the nucleus and binds to specific genes. 3 The bound protein stimulates the transcription of the gene into mRNA. 4 The mRNA is translated into a specific protein. 5 Steroid hormone interacting with an intracellular receptor Steroid hormone interacting with an intracellular receptor

12 Surface Receptors Receptors located on the surface of the membrane, 4 types: Receptors located on the surface of the membrane, 4 types: Chemically gated ion channels Chemically gated ion channels Enzymatic receptors Enzymatic receptors G-protein-linked receptors G-protein-linked receptors Integrins Integrins

13 Chemically Gated Ion Channels An ion channel receptor acts as a gate when the receptor changes shape 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 Ca 2+, through a channel in the receptor 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 Gate close Cellular response Gate open Gate close Ligand-gated ion channel receptor Plasma Membrane Signal molecule (ligand) Gate Closed Ions

14 Enzymatic Receptors Embedded in the plasma membrane, with their catalytic site exposed inside the cell. Embedded in the plasma membrane, with their catalytic site exposed inside the cell. Catalytic site activated when the signal molecule joins to the receptor. Catalytic site activated when the signal molecule joins to the receptor. Function as protein kinases (enzymes that phosphorylate proteins.) Function as protein kinases (enzymes that phosphorylate proteins.)

15 Receptor Tyrosine Kinases Signal molecule Signal-binding site CYTOPLASM Tyrosines Signal molecule  Helix in the Membrane Tyr Dimer Receptor tyrosine kinase proteins (inactive monomers) P P P P P P Tyr P P P P P P Cellular response 1 Inactive relay proteins Activated relay proteins Cellular response 2 Activated tyrosine- kinase regions (unphosphorylated dimer) Fully activated receptor tyrosine-kinase (phosphorylated dimer) 6 ATP 6 ADP

16 G-protein-linked Receptors Signal molecule joins to a receptor, the receptor activates a G proteinSignal molecule joins to a receptor, the receptor activates a G protein The activated G protein can then activate an ion channel or enzyme in the plasma membrane.The activated G protein can then activate an ion channel or enzyme in the plasma membrane. G protein Activated G protein Enzyme or ion channel Activated enzyme or ion channel G-protein-linked receptor Signal

17 Signal-binding site G-PROTEIN-LINKED RECEPTORS G-protein-linked receptor Plasma Membrane Enzyme G-protein (inactive) CYTOPLASM Cellular response Activated enzyme Activated receptor Signal molecule Inactive enzyme Segment that interacts with G proteins GDP GTP P iP i GDP

18 Second Messengers Some enzymatic receptors and most G-protein-linked receptors relay their message into the cell by activating other molecules or ions inside the cell. Some enzymatic receptors and most G-protein-linked receptors relay their message into the cell by activating other molecules or ions inside the cell. These molecules and ions, called second messengers, transmit the message within the cell. The 2 most common second messengers are cAMP and Ca++ These molecules and ions, called second messengers, transmit the message within the cell. The 2 most common second messengers are cAMP and Ca++

19 Signal Transduction Pathways Transduction usually involves multiple steps Transduction usually involves multiple steps Multistep pathways Multistep pathways Can amplify a signal Can amplify a signal Provide more opportunities for coordination and regulation Provide more opportunities for coordination and regulation The molecules that relay a signal from receptor to response are mostly proteins The molecules that relay a signal from receptor to response are mostly proteins The receptor activates another protein, which activates another, and so on, until the protein producing the response is activated 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 At each step, the signal is transduced into a different form, usually a conformational change

20 A Phosphorylation Cascade A Phosphorylation Cascade In many pathways, the signal is transmitted by a cascade of protein phosphorylations - phosphatase enzymes remove the phosphates 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 This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off Signal molecule Active protein kinase 1 Active protein kinase 2 Active protein kinase 3 Inactive protein kinase 1 Inactive protein kinase 2 Inactive protein kinase 3 Inactive protein Active protein Cellular response Receptor P P P P P P ATP ADP ATP PP Activated relay molecule A relay molecule activates protein kinase 1. 1 Active protein kinase 1 transfers a phosphate from ATP to an inactive molecule of protein kinase 2, thus activating this second kinase. 2 Active protein kinase 2 then catalyzes the phos- phorylation (and activation) of protein kinase 3. 3 Finally, active protein kinase 3 phosphorylates a protein (pink) that brings about the cell’s response to the signal. 4 Enzymes called protein phosphatases (PP) catalyze the removal of the phosphate groups from the proteins, making them inactive and available for reuse. 5 i i i Phosphorylation cascade

21 cAMP Second Messenger G-protein-signaling pathway 1. Signal molecule binds to surface receptor 2. Surface receptor activates a G protein 3. G protein activates the membrane-bound enzyme, adenylyl cyclase 4. Adenylyl cyclase catalyzes synthesis of camp, which binds to a target protein 5. Target protein initiates cellular change First messenger (signal molecule such as epinephrine) ATP GTP cAMP Protein kinase A Cellular responses G-protein-linked receptor Adenylyl cyclase G protein Second messenger

22 Cyclic AMP O –O–OO O N O O O OO P P P P PP O OO O O O OH CH 2 NH 2 N N N N N N N N N N N O O OO ATP Ch 2 CH 2 O OH P OO OO H2OH2O HO Adenylyl cyclase Phoshodiesterase Pyrophosphate Cyclic AMPAMP OH O i Cyclic AMP (cAMP) is one of the most widely used second messengers 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 Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response to an extracellular signal

23 Cyclic AMP Pathway

24 Calcium (Ca++) Pathways Calcium ions (Ca 2+ ) act as a second messenger in many pathways Calcium ions (Ca 2+ ) act as a second messenger in many pathways Calcium is an important second messenger because cells can regulate its concentration Calcium is an important second messenger because cells can regulate its concentration ATP EXTRACELLULAR FLUID ATP Mitochondrion Ca 2+ pump Plasma membrane CYTOSOL Endoplasmic reticulum (ER) Ca 2+ pump Ca 2+ pump High [Ca 2+ ] Key Nucleus Low [Ca 2+ ]

25 A signal transduction pathway may trigger an increase in calcium in the cytosol 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 second messengers Pathways leading to the release of calcium involve inositol triphosphate (IP 3 ) and diacylglycerol (DAG) as second messengers Calcium ions and Inositol Triphosphate (IP 3 )

26 Ca++ Pathway Signal molecule binds to surface receptor Signal molecule binds to surface receptor Surface receptor activates a G protein Surface receptor activates a G protein G protein activates the membrane-bound enzyme, phospholipase C G protein activates the membrane-bound enzyme, phospholipase C Phospholipase C catalyzes synthesis of inositol triphosphate, which stimulates release of Ca++ from ER Phospholipase C catalyzes synthesis of inositol triphosphate, which stimulates release of Ca++ from ER Released Ca++ initiates cellular change Released Ca++ initiates cellular change

27 Calcium and IP 3 in signaling pathways 2 3 IP 3 quickly diffuses through the cytosol and binds to an IP 3 – gated calcium channel in the ER membrane, causing it to open. 4 The calcium ions activate the next protein in one or more signaling pathways. 6 Calcium ions flow out of the ER (down their con- centration gradient), raising the Ca 2+ level in the cytosol. 5 DAG functions as a second messenger in other pathways. Phospholipase C cleaves a plasma membrane phospholipid called PIP 2 into DAG and IP 3. EXTRA- CELLULAR FLUID Signal molecule (first messenger) G protein G-protein-linked receptor Various proteins activated Endoplasmic reticulum (ER) Phospholipase C PIP 2 IP 3 DAG Cellular responses GTP Ca 2+ (second messenger) Ca 2+ IP 3 -gated calcium channel A signal molecule binds to a receptor, leading to activation of phospholipase C. 1 CYTOSOL

28 Fine-Tuning of the Response Multistep pathways have two important benefits: Multistep pathways have two important benefits: Amplifying the signal (and thus the response) Amplifying the signal (and thus the response) Contributing to the specificity of the response Contributing to the specificity of the response Enzyme cascades amplify the cell’s response Enzyme cascades amplify the cell’s response At each step, the number of activated products is much greater than in the preceding step At each step, the number of activated products is much greater than in the preceding step

29 Amplification Due to the many steps in the cell signaling process, one signal molecule can trigger a “cascade” effect Due to the many steps in the cell signaling process, one signal molecule can trigger a “cascade” effect

30 Cytoplasmic response to a signal: the stimulation of glycogen breakdown by epinephrine Glucose-1-phosphate (10 8 molecules) Glycogen Active glycogen phosphorylase (10 6 ) Inactive glycogen phosphorylase Active phosphorylase kinase (10 5 ) Inactive phosphorylase kinase Inactive protein kinase A Active protein kinase A (10 4 ) ATP Cyclic AMP (10 4 ) Active adenylyl cyclase (10 2 ) Inactive adenylyl cyclase Inactive G protein Active G protein (10 2 molecules) Binding of epinephrine to G-protein-linked receptor (1 molecule) Transduction Response Reception

31 Specificity of Cell Signaling Different kinds of cells have different collections of proteins 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 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 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 Pathway branching and “cross-talk” further help the cell coordinate incoming signals Signal molecule Receptor Relay molecules Response 1 Response 2Response 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

32 Signaling Efficiency: Scaffolding Proteins and Signaling Complexes Rather than relying on diffusion of large relay molecules such as proteins, many signal pathways are linked together physically by scaffolding proteins. Rather than relying on diffusion of large relay molecules such as proteins, many signal pathways are linked together physically by scaffolding proteins. Scaffolding proteins may themselves be relay proteins to which several other relay proteins attach. Scaffolding proteins may themselves be relay proteins to which several other relay proteins attach. This hardwiring enhances the speed, accuracy, and efficiency of signal transfer between cells. This hardwiring enhances the speed, accuracy, and efficiency of signal transfer between cells. Signal molecule Receptor Scaffolding protein Three different protein kinases Plasma membrane Figure 11.16

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