1. Cell Communication

2. Overview: The Cellular Internet Cell-to-cell communication is absolutely essential for multicellular organisms Nerve cells must communicate pain signals to muscle cells (stimulus) in order for muscle cells to initiate a response to pain

3. External Signals Signal Transduction Pathway

4. Yeast cells identify their mates by cell signaling (early evidence of signaling)  factor Receptor Exchange of mating factors. Each cell type secretes a mating factor that binds to receptors on the other cell type. 1 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 a cells. 2 3  factor Yeast cell, mating type a Yeast cell, mating type    a/  a a

5. Quorum Sensing

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. Cells in a multicellular organism (tissues, organs, systems) communicate via chemical messengers  A hormone is a chemical released by a cell in one part of the body, that sends out messages that affect cells in other parts of the organism All multicellular organisms produce hormones Plant hormones are also called phytohormones Hormones in animals are often transported in the blood Local and Long-Distance Signaling Fight or Flight

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

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. In other cases, animal cells  Communicate using local regulators (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

11. In long-distance signaling  Both plants and animals use hormones (e.g. Insulin) 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

12. Earl W. Sutherland  Discovered how the hormone epinephrine acts on cells The Three Stages of Cell Signaling

13. Sutherland’s Three Steps Sutherland suggested that cells receiving signals went through three processes  Reception  Transduction  Response

14. 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

15. Step One - Reception Reception occurs when a signal molecule binds to a receptor protein, causing it to change shape Receptor protein is on the cell surface

16. Step Two - Transduction The binding of the signal molecule alters the receptor protein in some way The signal usually starts a cascade of reactions known as a signal transduction pathway Multistep pathways can amplify a signal and help coordinate and regulate the cellular response.

17. Receptor Signaling molecule Activated relay molecule Phosphorylation cascade Inactive protein kinase 1 Active protein kinase 1 Active protein kinase 2 Active protein kinase 3 Inactive protein kinase 2 Inactive protein kinase 3 Inactive protein Active protein Cellular response ATP ADP ATP ADP ATP ADP PP P P P P i Figure 11.10

18. Step Three - Response Cell signaling leads to regulation of cytoplasmic activities or transcription Signaling pathways regulate a variety of cellular activities

19. Hormone (testosterone) EXTRACELLULAR FLUID Receptor protein DNA mRNA NUCLEUS CYTOPLASM Plasma membrane Hormone- receptor complex New protein Figure 11.6 Example of Pathway Steroid hormones bind to intracellular receptors 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 Testosterone receptor acts as a transcription factor: controls which genes are turned on and transcribed into mRNA.

20. 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

21. Signal response is terminated quickly by the reversal of ligand binding Termination of the Signal

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

23. G-protein-linked receptors G-protein-linked Receptor Plasma Membrane Enzyme G-protein (inactive) CYTOPLASM Cellular response Activated enzyme Activated Receptor Signal molecule Inactivate enzyme Segment that interacts with G proteins GDP GTP P iP i Signal-binding site Figure 11.7 GDP

24. (GPCRs) are the largest class of cell-surface receptors Works with the help of a G protein  Protein that binds GTP The G protein acts as an on/off switch  GDP: Guanosine diphosphate  GTP: Guanosine triphospate © 2011 Pearson Education, Inc.

25. Figure 11.7a G protein-coupled receptor Signaling molecule binding site Segment that interacts with G proteins Signaling molecules that use GCPR’s: epinephrine, neurotransmitters, Yeast mating factors, other hormones Signaling molecules that use GCPR’s: epinephrine, neurotransmitters, Yeast mating factors, other hormones GCPR’s play a role in embryonic development and sensory perception. Vision, smell, taste. Bacteria that cause cholera, pertussis, botulism,etc. secrete a toxin that interferes with G protein functioning.

26. 26

27. 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 Figure 11.7

28. Receptor tyrosine kinases (RTKs) are membrane receptors that attach phosphates to tyrosines. A receptor tyrosine kinase can trigger multiple signal transduction pathways at once.  Major difference to GCPR’s Abnormal functioning of RTKs is associated with many types of cancers © 2011 Pearson Education, Inc. Kinase: enzyme that catalyzes movement of phosphate groups.

29. Ion channel receptors Cellular response Gate open Gate close Ligand-gated ion channel receptor Plasma Membrane Signal molecule (ligand) Figure 11.7 Gate closed Ions

30. Second Messengers Extracellular signal molecule (ligand) that binds to the receptor is a “first messenger” Second messengers are small, nonprotein, water-soluble molecules or ions that spread throughout a cell by diffusion  Participate in GPCRs and RTKs pathways  Cyclic AMP and calcium ions are common second messengers © 2011 Pearson Education, Inc.

31. Cyclic AMP (cAMP) Plays a role in carrying the signal from epinephrine to the interior of the cell. That eventually yields a response in the breakdown of glycogen. Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response to an extracellular signal. The epinephrine itself does not stimulate adenylyl cyclase but the change in the protein epinephrine binds to does. © 2011 Pearson Education, Inc.

32. Many signal molecules trigger formation of cAMP Other components of cAMP pathways are G proteins, G protein-coupled 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 © 2011 Pearson Education, Inc.

33. Figure 11.12 G protein First messenger (signaling molecule such as epinephrine) G protein-coupled receptor Adenylyl cyclase Second messenger Cellular responses Protein kinase A GTP ATP cAMP

34. Second Messenger: Calcium Ions Ca 2+ : second messenger in many pathways  Muscle cell contraction  Secretion  Cell division  Plants: greening in response to light Important because cells can regulate concentration  Can be more than 10,000x more concentrated in blood and ECF than cytosol. © 2011 Pearson Education, Inc.

35. Figure 11.13 Mitochondrion EXTRACELLULAR FLUID Plasma membrane Ca 2  pump Nucleus CYTOSOL Ca 2  pump Endoplasmic reticulum (ER) ATP Low [Ca 2  ] High [Ca 2  ] Key

36. 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 additional second messengers  Could think of Ca 2+ as a third messenger but called a second messenger © 2011 Pearson Education, Inc. Where is the calcium coming from causing the increase?

37. G protein EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein-coupled receptor Phospholipase C DAG PIP 2 IP 3 (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Ca 2  GTP Figure 11.14-1

38. Figure 11.14-2 G protein EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein-coupled receptor Phospholipase C DAG PIP 2 IP 3 (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Ca 2  (second messenger) Ca 2  GTP

39. Figure 11.14-3 G protein EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein-coupled receptor Phospholipase C DAG PIP 2 IP 3 (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Various proteins activated Cellular responses Ca 2  (second messenger) Ca 2  GTP

40. Other pathways regulate the activity of enzymes rather than their synthesis  What does this mean? © 2011 Pearson Education, Inc.

41. Signaling pathways can also affect the overall behavior of a cell, for example, changes in cell shape  Yeast mating © 2011 Pearson Education, Inc.

42. Wild type (with shmoos)  Fus3  formin Mating factor activates receptor. Mating factor G protein-coupled receptor Shmoo projection forming Formin G protein binds GTP and becomes activated. 2 1 3 4 5 P P P P Formin Fus3 GDP GTP Phosphory- lation cascade Microfilament Actin subunit Phosphorylation cascade activates Fus3, which moves to plasma membrane. Fus3 phos- phorylates formin, activating it. Formin initiates growth of microfilaments that form the shmoo projections. RESULTS CONCLUSION Figure 11.17

43. Figure 11.17a Wild type (with shmoos)

44. Fine-Tuning of the Response There are four aspects of fine-tuning to consider  Amplification of the signal (and thus the response)  Specificity of the response  Overall efficiency of response, enhanced by scaffolding proteins  Termination of the signal © 2011 Pearson Education, Inc.

45. 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  Examples  Adenylyl cyclase catalyzes formation of many cAMP  Epinephrine binding can yield release of millions of glucose in muscle cells. © 2011 Pearson Education, Inc.

46. Figure 11.16 Reception Transduction Response Binding of epinephrine to G protein-coupled receptor (1 molecule) 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 Active protein kinase A (10 4 ) Inactive phosphorylase kinase Active phosphorylase kinase (10 5 ) Inactive glycogen phosphorylase Active glycogen phosphorylase (10 6 ) Glycogen Glucose 1-phosphate (10 8 molecules)

47. The Specificity of Cell Signaling and Coordination of the Response Different kinds of cells have different collections of proteins These different proteins allow cells to detect and respond to different signals Even the same signal can have different effects in cells with different proteins and pathways Pathway branching and “cross-talk” further help the cell coordinate incoming signals © 2011 Pearson Education, Inc.

48. Figure 11.18 Signaling molecule Receptor Relay molecules Response 1 Cell A. Pathway leads to a single response. Response 2Response 3 Response 4 Response 5 Activation or inhibition 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.

49. Specificity Example  Epinephrine  Leads to a liver response of glycogen breakdown  Leads to a heart response of contraction  Different set of proteins drives the reponse

50. 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 by grouping together different proteins involved in the same pathway In some cases, scaffolding proteins may also help activate some of the relay proteins © 2011 Pearson Education, Inc.

51. Figure 11.19 Signaling molecule Receptor Plasma membrane Scaffolding protein Three different protein kinases

52. Apoptosis integrates multiple cell-signaling pathways Apoptosis is programmed or controlled cell suicide Components of the cell are chopped up and packaged into vesicles that are digested by scavenger cells Apoptosis prevents enzymes from leaking out of a dying cell and damaging neighboring cells © 2011 Pearson Education, Inc.

53. Figure 11.20 2  m

54. Apoptosis in the Soil Worm C. elegans Apoptosis is important in shaping an organism during embryonic development The role of apoptosis in embryonic development was studied in C. elegans In C. elegans, apoptosis results when proteins that “accelerate” apoptosis override those that “put the brakes” on apoptosis © 2011 Pearson Education, Inc.

55. Figure 11.21 Mitochondrion Ced-9 protein (active) inhibits Ced-4 activity Receptor for death- signaling molecule Ced-4 Ced-3 Inactive proteins (a) No death signal Death- signaling molecule Ced-9 (inactive) Cell forms blebs Active Ced-4 Active Ced-3 Other proteases Nucleases Activation cascade (b) Death signal

56. Apoptotic Pathways and the Signals That Trigger Them Caspases are the main proteases (enzymes that cut up proteins) that carry out apoptosis Apoptosis can be triggered by  An extracellular death-signaling ligand  DNA damage in the nucleus  Protein misfolding in the endoplasmic reticulum © 2011 Pearson Education, Inc.

57. Apoptosis evolved early in animal evolution and is essential for the development and maintenance of all animals Apoptosis may be involved in some diseases (for example, Parkinson’s and Alzheimer’s); interference with apoptosis may contribute to some cancers  Some cases of melanoma have been linked to faulty versions of human Ced-4 protein © 2011 Pearson Education, Inc.