1. Cell Communication
Chapter 11

2. Recent Nobel Prizes in Medicine
2001 – Hartwell, Hunt, & Nurse – cyclin pathways and cell cycle regulation (yeast)
2002 – Brenner, Sulston, Horvitz – used C. elegans to elucidate the mechanism of apoptosis
2006 – Fire & Mello - used C.elegans to discover the pathway of RNA interference

3. Simon Sez… Signaling is a lot like the game “Simon Says…”
The signal is received: the game players hear: “Simon says take a step forward”
The signal is transduced: players must decide whether to step forward or not
The signal elicits a response: players step forward if the command was preceded by “Simon says”

4. 3 Stages of Signaling
Thesis: external signals are received & converted to responses within the cell
1. Reception
Signaling molecule binds to receptor protein = Shape Change
2. Transduction
Cascades of molecular interactions relay signals from receptor proteins to target molecules in the cell
3. Response
Regulation of transcription or cytoplasmic activities

5. Cell-to-Cell Communication
Critical for multicellular organisms
Trillions of cells must communicate in order to coordinate their activities
Recently, research is indicating how this communication can be corrupted, and cancer may occur
Although fairly unimportant for the AP Exam, crucial for understanding the breakthroughs in cancer and genetics that are occurring almost monthly now

6. Commonality? The same set of cell signaling mechanisms show up:
1. Embryonic development
2. Hormone action
Viagra’s effects are mediated through a STP (signal transduction pathway) called “cGMP Pathway”
3. Physiology
Cascades are responsible for blood vessel dilation & inflammatory response in allergic rxns
4. Oncogenesis (Onco- means cancer)
Cyclin pathway & Oncoproteins

7. 11.1 Introduction
Cell Signaling was probably 1st for mating between microorganisms
We can look at bacteria (Saccharomyces cerevisiae)
Responsible for bread, wine, & beer
2 Mating Types (a and α)
When their mating factors bind to an external receptor on the other mating type, the cells will grow closer together
Eventually, the cells fuse together (mating)
Results in an new cell that is genetic different from either mating type

9. Mechanism?
The signal at the cell surface gets transformed into a cellular response (mating), but how?
Signal Transduction Pathway (STP)
The mechanism of the STP in prokaryotes and complex mammals is strikingly identical

10. Local vs. Long-Distance
Sometimes there is direct contact
Other times, signals travel a short distance
Called Local Regulators
Influence cells in the vicinity
Example, growth factors – compounds that stimulate nearby target cells to grow & divide
Examples include Paracrine & Synaptic signaling

13. Long Distance Signaling
Hormones (Endocrine Signals)
Endocrinologists study??
Hormones travel by circulatory system vessels
Hormones vary widely in size
Another example, signal transmission along the length of a neuron

14. Long-Distance Signaling

15. Overview of Cell Signaling

16. 3 Stages of Cell Signaling
1. Reception
Target cell detects a signaling molecule coming from outside the cell
Cell surface receptor protein binds the signal molecule
2. Transduction
Signal molecule binds and causes conformational change in the surface receptor protein, which initiates the signal transduction pathway
Sometimes STP is a single step, but mostly multiple steps compose a STP

17. 3 Steps of Cell Signaling
3. Response
Transduced signal triggers a specific cellular response
This response can be almost any cellular activity
Catalysis by an enzyme
Rearrangement of the cytoskeleton
Activation of particular genes in the nucleus
Such as oncogene activation

18. Reception
Reception involves getting the signal to the correct receiver
Think of talking on a bus, others may hear, but you only want your listener to get the full message
Signaling molecules are complementary in shape to the receptor molecule
Signaling molecule sometimes called ligand
Molecule that specifically binds to another larger molecule

19. Reception (Page 2)
Usually receptor-ligand binding causes a conformational change in the receptor molecule
The conformational change activates the receptor & initiates a cascade event or STP
Can be likened to allosteric regulation of an enzyme
Shape change at one site = promotion/inhibition of enzyme activity

20. 2 Types of Signal Receptors
1. Plasma Membrane Receptors
G Protein-Coupled Receptors
Receptor Tyrosine Kinase
Ion Channel Receptors
2. Intracellular Receptors
Chemical messengers that pass through membrane
Steroid & thyroid hormones
Tend to carry out complete signal transduction by themselves

21. G Protein-Coupled Receptor (GPCR)
Def. – Plasma membrane receptor that works with the help of a G protein
G protein – protein that binds GTP
Common receptor
Found in yeast mating factors, epinephrine, & assorted other hormones & neurotransmitters
Also responsible for the symptoms of many bacterial diseases, such as cholera & botulism
Similarity between prokaryotes and eukaryotes evidences early evolution of G protein receptor molecules
60% of all meds exert their influence by G protein pathways

22. G Protein-Coupled Receptors (Page 2)
All G Proteins have same basic structure
7 α-helices spanning the membrane
Loops on either face of the membrane for binding sites

23. G Protein-Coupled Receptor
Signaling molecule binds, causing conformational change in receptor.
Inactive G protein binds & is activated by GTP formation.
G Protein also functions as an GTPase, so makes itself inactive
in the absence of continuing signals

24. Receptor Tyrosine Kinase (RTK)
Enzymatic activity
Kinase – enzyme that catalyzes transfer of phosphate group
Here, Phosphate is transferred from ATP to Tyrosines (type of amino acid)
Rapid amplification
1 tyrosine kinase complex can activate 10 or more STPs or cellular responses

25. Receptor Tyrosine Kinase
Dimerization

26. Ion Channel Receptor
Membrane receptor with a region that acts as a “gate” when the receptor changes shape.
When the signal molecule binds, gate opens or closes
Allows or blocks flow of specific ions
Such as Na+ or Ca2+
Important in the nervous system
Neurotransmitters & synaptic transmission
Could be controlled by electrical signals instead of chemicals (Voltage-gated ion channels)

27. Ion Channel Receptor

28. Intracellular Receptor
Testosterone
-- Example of steroid
Most intracellular receptor signals do the entire transduction on their own
Testosterone behaving as a transcription factor
-- controls which genes (DNA)
are transcribed into mRNA

29. 11.3 Transduction Multistep Pathway Signal amplification
One molecule in the series,
passes signal to multiple molecules
of the next component
Think of dominoes
Small Signal amount  Large cellular response

30. Amplification & Pathways

31. 11.3 Transduction (Page 2)
Incoming signal is NOT physically passed along a signaling pathway
Certain information is passed on
By transduction (change form) into a different form of each protein in the cascade
Typically transduction brought about by phosphorylation (remember from CH8?)

32. 11.3 Transduction (Page 3)
Signal Transduction Pathways often involve a phosphorylation cascade
A series of different molecules in a pathway are phosphorylated in turn, each molecule adding a phosphate group to the next one in line
As each molecule is phosphorylated, it becomes active
As each molecule transfers the phosphate, it becomes inactive again
Involves enzymes called protein kinases
General term for an enzyme that transfers phosphate from ATP to a protein

33. Phosphorylation Cascade

34. Protein Kinases
Phosphorylation & dephosphorylation of proteins is the primary mechanism of cellular activity regulation
2% of genomic content codes for protein kinases
Abnormal kinase activity leads to cancer
Protein Phosphatases
Enzymes that remove phosphate from proteins
Recycles pathway components

35. GF = Growth factor
RTK = Receptor Tyrosine Kinase
Ras = G Protein
-- Associated with
tumor growth
Rho = G protein
Traf = Tumor necrosis factor

36. RTK = Receptor Tyrosine Kinase
GPCR – G-protein coupled receptor
PDK1 = Protein dehydrogenase kinase
Akt = Protein kinase
-- Involved in apoptosis
Apoptosis = Programmed cell death

37. Second Messengers
Capable of initiating phosphorylation cascade on their own
Signal pathway members that are nonprotein, small, and water-soluble
Cyclic AMP or Calcium ions
Called 2nd since the membrane receptor is called 1st messenger
1st messenger can only be RTK or GPCR

38. Cyclic AMP Epinephrine (First Messenger) 1. Binds to GPCR
2. Activates G protein
3. Adenylyl cyclase converts
ATP  cyclicAMP
-- Since 1 GPCR can affect multiple G
proteins, the epinephrine signal is
amplified through this pathway
Why would epinephrine want its signal amplified?

39. Zimbabwe’s Cholera Epidemic
We can explain how (vibrio cholera) actually creates its symptoms
Cholera bacteria (ingested via infected H2O) secretes an enzyme (toxin) that modifies G protein
This G protein regulates cell tonicity and water secretion
Toxin interferes with GTP conversion (deactivation)
So GTP keeps activating adenylyl cyclase  cyclicAMP
Water and salt secretion continues when it should have shut off long ago
Amplification?
Patients require significant rehydration to compensate for fluid and electrolyte loss

40. Calcium Ions More common 2nd messenger than cyclicAMP
Effective since intracellular concentration is so low, that any absolute change in numbers = a significant change in percentage terms
Muscle cell contractions, secretion, cell division

41. 11.4 Response STP usually leads to a regulation of cellular activities
Response may occur in the cytoplasm or nucleus
2 Types of typical response:
1. Enzyme activity is regulated (turned on or off)
2. Synthesis of enzymes is regulated (promoted or inhibited)

42. Transcription factors
DNA  RNA  Protein (Central Dogma)
DNA  mRNA = Transcription
mRNA  Protein = Translation
Transcription factors (TF) control which genes are transcribed
Which genes are converted into mRNA
Which genes are turned on or off
Usually TFs affect multiple genes
Typically, the final molecule in a STP is a transcription factor

44. Signal Amplification 2 Reasons for multistep pathways:
2. Specificity of Cell Signaling
Signal Amplification
Intermediates in the pathway exist in active form long enough to activate numerous other molecules before becoming inactive

45. Signal Specificity Different cells have different proteins
Different receptor proteins
Different relay proteins or molecules
Allows different cells to have a different response to the same signal
In Liver cells: Epinephrine = glycogen breakdown  glucose production
In cardiac muscle: Epinephrine = rapid & enhanced contractions

47. Scaffolding Proteins
Definition - large relay proteins that physically hold several other relay proteins
Physical proximity significantly increases efficiency of signal transfer
Scaffolding in brain cells hold together networks of signaling-pathway proteins at synapses

48. Signal Termination
Just as certain molecules are activated, they too can be inactivated
Signal molecule leaves the receptor = inactivation
Protein phosphatases inactivate phosphorylated protein kinases
Soon the target cell is returned to its inactive form, and ready to be activated again.