1. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Chapter 11: Cell Communication “No man’s an island and neither is a cell.”

2. 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

3. 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

4. LE 11-3 Plasma membranes Gap junctions between animal cells Cell junctions Cell-cell recognition Plasmodesmata between plant cells

5. 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

6. 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

7. 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 Animation: Overview of Cell Signaling

8. LE 11-5_1 EXTRACELLULAR FLUID Reception Plasma membrane Transduction CYTOPLASM Receptor Signal molecule

9. LE 11-5_2 EXTRACELLULAR FLUID Reception Plasma membrane Transduction CYTOPLASM Receptor Signal molecule Relay molecules in a signal transduction pathway

10. 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

11. 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

12. 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

13. 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

14. 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

15. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Transmembrane Receptor Structure All three transmembrane receptor types have the same basic structural features: 1) an extracellular domain (ECD), 2) a transmembrane domain (TMD), and 3) an intracellular domain (ICD) ECD  binds ligand TMD  anchors protein in the membrane ICD  shape change occurs to relay internalization of signal (Extracellular Space) (Cell Membrane) (Cytoplasm)

16. 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

17. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

18. Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines A receptor tyrosine kinase can trigger multiple signal transduction pathways at once Reminder: A kinase is a class of enzyme that phosphorylates its substrate

19. LE 11-7b Signal molecule  Helix in the membrane Signal-binding site Tyr Tyrosines Receptor tyrosine kinase proteins (inactive monomers) CYTOPLASM Tyr Activated tyrosine- kinase regions (unphosphorylated dimer) Signal molecule Dimer Fully activated receptor tyrosine-kinase (phosphorylated dimer) Tyr P P P P P P ATP 6 ADP Tyr P P P P P P Inactive relay proteins Cellular response 2 Cellular response 1 Activated relay proteins 6

20. 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 Ca 2+, through a channel in the receptor

21. LE 11-7c Signal molecule (ligand) Gate closed Ions Ligand-gated ion channel receptor Plasma membrane Gate closed Gate open Cellular response

22. 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

23. 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 https://www.youtube.com/watch?v=WRv9b7S6Hm8 At each step, the signal is transduced into a different form, usually a conformational change

24. 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; these are the counterparts to kinases This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off

25. 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 Phosphorylation cascade ATP PP P i ADP ATP PP P i ADP ATP PP P i P P P

26. 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

27. 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

28. LE 11-9 ATPCyclic AMPAMP Adenylyl cyclase Pyrophosphate PP i Phosphodiesterase H2OH2O

29. 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

30. 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

31. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Calcium ions and Inositol Triphosphate (IP 3 ) Calcium ions (Ca 2+ ) act as a second messenger in many pathways Calcium is an important second messenger because cells can regulate its concentration

32. 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 (IP 3 ) and diacylglycerol (DAG) as second messengers Animation: Signal Transduction Pathways Animation: Signal Transduction Pathways

33. LE 11-12_1 CYTOSOL Ca 2+ Endoplasmic reticulum (ER) IP 3 -gated calcium channel IP 3 (second messenger) DAG PIP 2 G-protein-linked receptor Phospholipase C G protein Signal molecule (first messenger) EXTRACELLULAR FLUID GTP

34. LE 11-12_2 CYTOSOL Ca 2+ Endoplasmic reticulum (ER) IP 3 -gated calcium channel IP 3 (second messenger) DAG PIP 2 G-protein-linked receptor Phospholipase C G protein Signal molecule (first messenger) EXTRACELLULAR FLUID GTP Ca 2+ (second messenger)

35. LE 11-12_3 CYTOSOL Ca 2+ Endoplasmic reticulum (ER) IP 3 -gated calcium channel IP 3 (second messenger) DAG PIP 2 G-protein-linked receptor Phospholipase C G protein Signal molecule (first messenger) EXTRACELLULAR FLUID GTP Ca 2+ (second messenger) Various proteins activated Cellular re- sponses

36. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Concept 11.4: Response: Cell signaling leads to regulation of cytoplasmic activities or transcription 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

37. 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

38. LE 11-14 Reception Growth factor Receptor Phosphorylation cascade Transduction CYTOPLASM Inactive transcription factor Active transcription factor P Response Gene mRNA DNA NUCLEUS

39. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Control of Cell Response: Fine-Tuning of the Response – Amplification & Specificity Multistep pathways have two important benefits: 1. 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 http://highered.mcgraw- hill.com/sites/0072437316/student_view0/chapter7 /animations.html# 2. Contributing to the specificity of the response:

40. LE 11-13 Binding of epinephrine to G-protein-linked receptor (1 molecule) Reception Transduction Inactive G protein Active G protein (10 2 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (10 2 ) ATP Cyclic AMP (10 4 ) Inactive protein kinase A Inactive phosphorylase kinase Active protein kinase A (10 4 ) Active phosphorylase kinase (10 5 ) Active glycogen phosphorylase (10 6 ) Inactive glycogen phosphorylase Glycogen Response Glucose-1-phosphate (10 8 molecules)

41. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 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

42. LE 11-15 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 Same ligand may bind more than one type of receptor

43. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Control of the Cell Response: 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

44. LE 11-16 Signal molecule Plasma membrane Receptor Scaffolding protein Three different protein kinases

45. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Control of Cell Response: 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 Reception of another signal that inactivates the first pathway (phosphorylation/dephosphorylation) Additionally, when certain receptors become modified, they can become internalized and ubiquitinated (tagged for degradation) - effectively terminating the cascade pathway

46. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Concept 11.5: Apoptosis Also known as programmed cell death (PCD) Different from necrosis – cells don’t rupture (lyse), thus, cellular contents are not released to the surrounding environment

47. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Caspases – the main proteases (enzymes that degrade proteins) of apoptosis