Cell Communication Overview: Signaling Mechanisms and Pathways

1. Chapter 11 Cell Communication

2. Overview: The Cellular Internet • Cell-to-cell communication • Is absolutely essential for multicellular organisms

3. Biologists • Have discovered some universal mechanisms of cellular regulation Figure 11.1

4. Concept 11.1: External signals are converted into responses within the cell

5. Exchange of mating factors. Each cell type secretes a mating factor that binds to receptors on the other cell type. factor 3 1 2 Receptor a  factor Yeast cell, mating type a Yeast cell, mating type Mating. Binding of the factors to     receptors induces changes      in the cells that     lead to their     fusion.  a New a/ cell. The nucleus of the fused cell includes all the genes from the a and a cells. a/ Figure 11.2 Evolution of Cell Signaling • Yeast cells • Identify their mates by cell signaling

6. Signal transduction pathways • Convert signals on a cell’s surface into cellular responses • Are similar in microbes and mammals, suggesting an early origin

7. Local and Long-Distance Signaling • Cells in a multicellular organism • Communicate via chemical messengers

8. 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. • Animal and plant cells • Have cell junctions that directly connect the cytoplasm of adjacent cells

9. 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

10. Local signaling Target cell Electrical signal along nerve cell triggers release of neurotransmitter Neurotransmitter diffuses acrosssynapse Secretory vesicle Local regulator diffuses through extracellular fluid Target cell is stimulated (b) Synaptic signaling. A nerve cell releases neurotransmitter molecules into a synapse, stimulating the target cell. (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. Figure 11.4 A B • In other cases, animal cells • Communicate using local regulators

11. Long-distance signaling Blood vessel Endocrine cell Hormone travels in bloodstream to target cells Target cell (c) Hormonal signaling. Specialized endocrine cells secrete hormones into body fluids, often the blood. Hormones may reach virtually all body cells. Figure 11.4 C • In long-distance signaling • Both plants and animals use hormones

12. The Three Stages of Cell Signaling: A Preview • Earl W. Sutherland • Discovered how the hormone epinephrine acts on cells

13. Sutherland suggested that cells receiving signals went through three processes • Reception • Transduction • Response

14. EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 2 3 Reception Transduction Response Receptor Activation of cellular response Relay molecules in a signal transduction pathway Signal molecule Figure 11.5 • Overview of cell signaling

15. Concept 11.2: Reception: A signal molecule binds to a receptor protein, causing it to change shape

16. 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

17. Intracellular Receptors • Intracellular receptors • Are cytoplasmic or nuclear proteins

18. Signal molecules that are small or hydrophobic • And can readily cross the plasma membrane use these receptors

19. Hormone (testosterone) EXTRACELLULAR FLUID 1 The steroid hormone testosterone passes through the plasma membrane. Plasma membrane Receptor protein 2 Testosterone binds to a receptor protein in the cytoplasm, activating it. Hormone- receptor complex 3 The hormone- receptor complex enters the nucleus and binds to specific genes. DNA mRNA 4 The bound protein stimulates the transcription of the gene into mRNA. NUCLEUS New protein 5 The mRNA is translated into a specific protein. CYTOPLASM Figure 11.6 • Steroid hormones • Bind to intracellular receptors

20. Receptors in the Plasma Membrane • There are three main types of membrane receptors • G-protein-linked • Tyrosine kinases • Ion channel

21. Signal-binding site Segment that interacts with G proteins Inctivate enzyme ActivatedReceptor G-protein-linked Receptor Signal molecule Plasma Membrane GDP G-protein(inactive) GTP GDP CYTOPLASM Enzyme Activated enzyme GTP GDP Pi Cellular response Figure 11.7 • G-protein-linked receptors

22. Signal-binding sitea Signalmolecule Signal molecule Helix in the Membrane Tyr Tyr Tyr Tyr Tyrosines Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Receptor tyrosinekinase proteins(inactive monomers) Dimer CYTOPLASM Activatedrelay proteins Cellularresponse 1 Tyr Tyr Tyr Tyr Tyr Tyr P P Tyr P Tyr Tyr Tyr Tyr P Tyr Tyr Tyr P P P Tyr Tyr Tyr Tyr Tyr P Tyr Tyr Tyr Cellularresponse 2 P P P Tyr Tyr P 6 ATP 6 ADP Activated tyrosine- kinase regions (unphosphorylated dimer) Fully activated receptor tyrosine-kinase (phosphorylated dimer) Inactiverelay proteins Figure 11.7 • Receptor tyrosine kinases

23. Gate closed Signalmolecule(ligand) Ions Ligand-gated ion channel receptor Plasma Membrane Gate open Cellularresponse Gate close Figure 11.7 • Ion channel receptors

24. Concept 11.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell • Multistep pathways • Can amplify a signal • Provide more opportunities for coordination and regulation

25. Signal Transduction Pathways • At each step in a pathway • The signal is transduced into a different form, commonly a conformational change in a protein

26. Protein Phosphorylation and Dephosphorylation • Many signal pathways • Include phosphorylation cascades

27. 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

28. Signal molecule A relay molecule activates protein kinase 1. Receptor Activated relay molecule 4 1 3 5 2 Inactive protein kinase 1 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 1 Active protein kinase 2 then catalyzes the phos- phorylation (and activation) of protein kinase 3. Inactive protein kinase 2 ATP Phosphorylation cascade P Active protein kinase 2 ADP PP P i Enzymes called protein phosphatases (PP) catalyze the removal of the phosphate groups from the proteins, making them inactive and available for reuse. Inactive protein kinase 3 Finally, active protein kinase 3 phosphorylates a protein (pink) that brings about the cell’s response to the signal. ATP P ADP Active protein kinase 3 PP P i Inactive protein ATP P ADP Active protein Cellular response PP P  i • A phosphorylation cascade Figure 11.8

29. Small Molecules and Ions as Second Messengers • Second messengers • Are small, nonprotein, water-soluble molecules or ions

30. NH2 NH2 NH2 N N N N N N N N N N N O O O N O Adenylyl cyclase Phoshodiesterase CH2 O HO Ch2 P –O O P O P P O CH2 O O O O O O O O O P Pyrophosphate H2O O O P P i OH OH OH OH OH ATP Cyclic AMP AMP Figure 11.9 Cyclic AMP • Cyclic AMP (cAMP) • Is made from ATP

31. First messenger (signal molecule such as epinephrine) Adenylyl cyclase G protein GTP G-protein-linked receptor ATP cAMP Protein kinase A Cellular responses • Many G-proteins • Trigger the formation of cAMP, which then acts as a second messenger in cellular pathways Figure 11.10

32. Calcium ions and Inositol Triphosphate (IP3) • Calcium, when released into the cytosol of a cell • Acts as a second messenger in many different pathways

33. EXTRACELLULAR FLUID Plasma membrane Ca2+pump ATP Mitochondrion Nucleus CYTOSOL Ca2+pump Endoplasmic reticulum (ER) ATP Ca2+pump Key High [Ca2+] Low [Ca2+] Figure 11.11 • Calcium is an important second messenger • Because cells are able to regulate its concentration in the cytosol

34. Other second messengers such as inositol triphosphate and diacylglycerol • Can trigger an increase in calcium in the cytosol

35. 3 2 1 4 6 5 A signal molecule binds to a receptor, leading to activation of phospholipase C. DAG functions as a second messenger in other pathways. Phospholipase C cleaves a plasma membrane phospholipid called PIP2 into DAG and IP3. EXTRA- CELLULAR FLUID Signal molecule (first messenger) G protein DAG GTP PIP2 G-protein-linked receptor Phospholipase C IP3 (second messenger) IP3-gated calcium channel Endoplasmic reticulum (ER) Various proteins activated Cellularresponse Ca2+ Ca2+ (second messenger) The calcium ions activate the next protein in one or more signaling pathways. IP3 quickly diffuses through the cytosol and binds to an IP3– gated calcium channel in the ER membrane, causing it to open. Calcium ions flow out of the ER (down their con- centration gradient), raising the Ca2+ level in the cytosol. Figure 11.12

36. Concept 11.4: Response: Cell signaling leads to regulation of cytoplasmic activities or transcription

37. Cytoplasmic and Nuclear Responses • In the cytoplasm • Signaling pathways regulate a variety of cellular activities

38. 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) • Cytoplasmic response to a signal Figure 11.13

39. Growth factor Reception Receptor Phosphorylation cascade Transduction CYTOPLASM Inactive transcription factor Active transcription factor Response P DNA Gene mRNA NUCLEUS Figure 11.14 • Other pathways • Regulate genes by activating transcription factors that turn genes on or off

40. Fine-Tuning of the Response • Signal pathways with multiple steps • Can amplify the signal and contribute to the specificity of the response

41. Signal Amplification • Each protein in a signaling pathway • Amplifies the signal by activating multiple copies of the next component in the pathway

42. 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

43. Signalmolecule Receptor Relaymolecules Response 2 Response 1 Response 3 Cell B. Pathway branches, leading to two responses Cell A. Pathway leads to a single response Activationor inhibition Response 4 Response 5 Cell C. Cross-talk occurs between two pathways Cell D. Different receptor leads to a different response Figure 11.15 • Pathway branching and “cross-talk” • Further help the cell coordinate incoming signals

44. Signalmolecule Plasmamembrane Receptor Threedifferentproteinkinases Scaffoldingprotein Figure 11.16 Signaling Efficiency: Scaffolding Proteins and Signaling Complexes • Scaffolding proteins • Can increase the signal transduction efficiency

45. Termination of the Signal • Signal response is terminated quickly • By the reversal of ligand binding