1. Sustaining Proliferative Signaling and Evading Growth Suppressors
Oct 19, 2017

2. Hallmarks of Cancer, 2011

3. Signal Transduction Proteins may Relay the signal to the next protein
Scaffold proteins bring components together to be more efficient

4. Signal Transduction
The signal may be transduced into a more suitable form
Amplification – many copies of the signal may be produced
Signaling cascade – signal transduction with multiple amplification steps

5. Signal Transduction
Signals may come from more than one pathway and need to be integrated
The signals may spread from one pathway to another (aka cross-talk)

6. Signal Transduction
The signaling proteins may be anchored to a particular location where they are needed
The activity of other signaling proteins may be modulated thereby regulating the strength of the final signal

7. Intracellular Signaling Switches
Molecular Switches

8. Intracellular Signaling Switches
Phosphorylation cascades
2 types:
Serine/Threonine kinases
Tyrosine kinases

9. Intracellular Signaling Switches
2 forms of GTPases:
Trimeric GTP-binding proteins (G-Proteins)
Monomeric GTP-binding proteins (Monomeric GTPases)

10. Monomeric GTPases GAP – GTPase-activating protein
GEF – Guanine nucleotide exchange factor

11. Signal Integration
2 different signals are needed to create the downstream signal
Coincidence detector

12. Other Signaling Methods
1. Other Molecular switches include binding of cAMP or Ca+2
2. Other covalent modification such as ubiquitination
3. Some signaling molecules don’t have direct enzymatic activity but just bind with other proteins and aid them in further interaction

13. Scaffold Proteins
A single Extracellular signal binding to 1 receptor often activates multiple parallel signaling pathways and affect multiple cell behaviors
How do you avoid cross-talk?
Scaffold Proteins
Bind groups of interacting signaling proteins into signaling complexes

14. Assembly on an Activated Receptor
Phosphorylation of cytoplasmic receptor tail allows binding of signaling proteins
Advantage: Rapid assembly and disassembly

15. Phospholipid Signaling

18. -Phosphatidyl inositol is found in the cytosolic monolayer

20. Interaction Domains
Interaction domains on signaling proteins allow them to bind to other proteins in the pathway to create a signaling pathway
Each domain binds to a different structural motif
-short peptides
-covalent modification
-another protein domain

21. Domain Shuffling Allows for new protein-protein interactions to evolve
New gene responsible for a new protein with a new function

22. Types of Interaction Domains
SH2 – Src homology 2 domain
-binds to phosphorylated tyrosines
SH3 – Src homology 3 domain
-Binds to short proline-rich amino acid sequence
PH – Pleckstrin homology
-Binds to the charged head groups of specific phospholipids
Adaptors – contain 2 or more interaction domains and serve just to bring the other proteins together

23. Insulin Receptor Complex

25. Lipid Rafts
Help to cluster receptors and intracellular signaling proteins

26. Receptor Concentration

28. Methods of Receptor Concentration

29. Types of Signaling Responses
Graded
Switch-like

30. Progesterone Signaling in Frog Oocytes

31. Progesterone Signaling in Frog Oocytes
Two possible mechanisms!!!
Oocytes need to be tested individually
Result: All or None (C)

32. Effector Molecule Effects
Graded responses can also be very steep
Depends on the
Strength of the signal
Number of Effector molecules (signals)
Example:
PKA (cAMP-dependent protein kinase)
-4 cAMP molecules
Cooperative response

33. Effector Molecule Effects
Graded responses can steepened
Also occurs if the Signaling molecule both:
Activates an enzyme
Inhibits another enzyme
Example:
Adrenaline, cAMP increases are a result to receptor binding
Promotes glycogen breakdown
Inhibits glycogen synthesis
Cooperative response

34. Feedback Loops
Positive Feedback – the output stimulates its own production
Negative Feedback – the output inhibits its own production
Timing – Vary
Signaling – the feedback could involve either intracellular or extracellular signals

35. Positive Feedback -Necessary for All-or-None responses
-Once the feedback molecule reaches a critical concentration, a new level of activity/production occurs

36. Positive Feedback
Once a system has reach a high level of activation, the condition can persist even in the absence of the signal
A transient signal can produce a strong enough positive feedback to continue its effect for the life of the cell
Seen in cell fate/development

37. Negative Feedback Activating a phosphatase to inactivate the Enzyme
The length of the delay of the negative feedback can affect the activity of the enzyme differently
-a short delay causes a strong brief response
-a long delay causes oscillations while the signal is present

38. Desensitization
A decrease in the cell’s response to a given level of stimulus over a prolonged exposure

39. Faculty Candidates Monday, Oct 23
11am-12pm Teaching Demonstration SSN381
2:45-3:30pm Meet with Students Bio Office
4-5pm Research Seminar Mer112
Friday, Oct 27
After lunch Meet with Students Bio Office
Monday, Oct 30