1. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Objective 12: TSWBAT construct explanations of cell communication through cell-to-cell direct contact or through chemical signaling. Objective 13: TSWBAT describe a model that expresses the key elements of signal transduction pathways.

2. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Overview: The Cellular Internet Cell-to-cell communication is absolutely essential for multicellular organisms Biologists have discovered some universal mechanisms of cellular regulation

3. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings External signals are converted into responses within the cell 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. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Evolution of Cell Signaling Yeast cells – Identify their mates by cell signaling  factor Receptor Exchange of mating factors. 1 Mating. New a/  cell. 2 3  factor Yeast cell, mating type a Yeast cell, mating type    a/  a a Figure 11.2

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. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Plasma membranes Plasmodesmata between plant cells Gap junctions between animal cells Figure 11.3 (a) Cell junctions. Both animals and plants have cell junctions that allow molecules to pass readily between adjacent cells without crossing plasma membranes.

7. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Figure 11.3 (b) Cell-cell recognition. Two cells in an animal may communicate by interaction between molecules protruding from their surfaces. In local signaling, animal cells may communicate via direct contact

8. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings In other cases, animal cells communicate using local regulators, messenger molecules that travel short distances. (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. Local regulator diffuses through extracellular fluid Target cell Secretory vesicle Electrical signal along nerve cell triggers release of neurotransmitter Neurotransmitter diffuses across synapse Target cell is stimulated Local signaling Figure 11.4 A B

9. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings In long-distance signaling both plants and animals use hormones 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. Long-distance signaling Blood vessel Target cell Endocrine cell Figure 11.4 C

10. 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

11. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings EXTRACELLULAR FLUID Receptor Signal molecule Relay molecules in a signal transduction pathway Plasma membrane CYTOPLASM Activation of cellular response Figure 11.5 Overview of cell signaling Reception 1 Transduction 2 Response 3

12. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Reception: A signal molecule binds to a receptor protein, causing it to change shape The binding between 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

13. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Intracellular Receptors Intracellular receptors are cytoplasmic or nuclear proteins Signal molecules that are small or hydrophobic and can readily cross the plasma membrane use these 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.

14. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Hormone (testosterone) EXTRACELLULAR FLUID Receptor protein DNA mRNA NUCLEUS CYTOPLASM Plasma membrane Hormone- receptor complex New protein Figure 11.6 1 The steroid hormone testosterone passes through the plasma membrane. The bound protein stimulates the transcription of the gene into mRNA. 4 The mRNA is translated into a specific protein. 5 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

15. 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 – Tyrosine kinases – Ion channel

16. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings G-protein-linked receptors G-protein-linked Receptor Plasma Membrane Enzyme G-protein (inactive) CYTOPLASM Cellular response Activated enzyme Activated Receptor Signal molecule Inactivated enzyme Segment that interacts with G proteins GDP GTP P iP i Signal-binding site Figure 11.7 GDP

17. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Receptor tyrosine kinases Signal molecule Signal-binding sites 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 Figure 11.7

18. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Ion channel receptors 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 Cellular response Gate open Gate close Ligand-gated ion channel receptor Plasma Membrane Signal molecule (ligand) Figure 11.7 Gate closed Ions

19. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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 Provide more opportunities for coordination and regulation

20. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Signal Transduction Pathways 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, until the protein producing the response is activated At each step in a pathway the signal is transduced into a different form, commonly a conformational change in a protein

21. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Protein Phosphorylation and Dephosphorylation Many signal pathways include phosphorylation cascades In this process a series of protein kinases add a phosphate to the next one in line, activating it phosphatase enzymes then remove the phosphates This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off

22. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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 ATP ADP ATP PP Activated relay molecule i Phosphorylation cascade P P i i P A phosphorylation cascade Figure 11.8 A relay molecule activates protein kinase 1. 1 2 Active protein kinase 1 transfers a phosphate from ATP to an inactive molecule of protein kinase 2, thus activating this second kinase. 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

23. 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 imitated by G-protein-linked receptors and receptor tyrosine kinases

24. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Cyclic AMP (cAMP) is one of the most widely used second messengers Adenylyl cyclase (enzyme in the plasma membrane) converts ATP to cAMP in response to and extracellular signal. Figure 11.9 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 Phosphodiesterase Pyrophosphate Cyclic AMPAMP OH O i

25. 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

26. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings ATP GTP cAMP Protein kinase A Cellular responses G-protein-linked receptor Adenylyl cyclase G protein First messenger (signal molecule such as epinephrine) Figure 11.10

27. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Calcium ions and Inositol Triphosphate (IP 3 ) Calcium, when released into the cytosol of a cell acts as a second messenger in many different pathways Calcium is an important second messenger because cells can regulate its concentration

28. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings EXTRACELLULAR FLUID Plasma membrane ATP CYTOSOL ATP Ca 2+ pump Endoplasmic reticulum (ER) Nucleus Mitochondrion Key High [Ca 2+ ]Low [Ca 2+ ] Figure 11.11

29. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Other second messengers such as inositol triphosphate and diacylglycerol which can trigger an increase in calcium in the cytosol

30. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Figure 11.12 3 21 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. A signal molecule binds to a receptor, leading to activation of phospholipase C. 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 (second messenger) DAG Cellular response GTP Ca 2+ (second messenger) Ca 2+ IP 3 -gated calcium channel

31. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Response: Cell signaling leads to regulation of cytoplasmic activities or transcription In the cytoplasm signaling pathways regulate a variety of cellular activities The cell’s response to an extracellular signal is sometimes called the “output response” Ultimately, a signal transduction pathway leads to regulation of one or more cellular activities

32. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Cytoplasmic response to a signal Figure 11.13 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

33. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Other pathways regulate genes by activating transcription factors that turn genes on or off Reception Transduction Response mRNA NUCLEUS Gene P Active transcription factor Inactive transcription factor DNA Phosphorylation cascade CYTOPLASM Receptor Growth factor Figure 11.14

34. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Fine-Tuning of the Response Signal pathways with multiple steps can amplify the signal and contribute to the specificity of the response Signal amplification occurs when enzyme cascades amplify the cell’s response At each step, the number of activated products is much greater than in the preceding step

35. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The Specificity of Cell Signaling The different combinations of proteins in a cell give the cell great specificity in both the signals it detects and the responses it carries out 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

36. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Response 1 Response 4Response 5 Response 2 Response 3 Signal molecule Cell A. Pathway leads to a single response Cell B. Pathway branches, leading to two responses Cell C. Cross-talk occurs between two pathways Cell D. Different receptor leads to a different response Activation or inhibition Receptor Relay molecules Figure 11.15

37. 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 and they can increase the signal transduction efficiency Signal molecule Receptor Scaffolding protein Three different protein kinases Plasma membrane Figure 11.16

38. 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