1. Sustaining Proliferative Signaling and Evading Growth Suppressors
Oct

2. Hallmarks of Cancer, 2011

4. Communication in Simple cells
Quorum sensing in bacteria resulting in motility, antibiotic production, spore formation, or conjugation

5. Signaling Molecules Molecule Types:
Proteins, Small peptides, and amino acids
Nucleotides
Retinoids and Fatty acid derivatives
Dissolved gases, nitric oxide and carbon monoxide
Molecule Activation:
Released through exocytosis
Diffusion
Displayed on the external cell surface
Release of transmembrane proteins via cleavage

6. Extracellular Signal Molecule Binding
Hydrophilic molecules bind at the cell surface
Hydrophobic and small molecules mass bind in the cell interior

7. Forms of Intercellular Signaling
Autocrine – a cell responding to a signal that they produce

8. Endocrine vs. Neuronal Strategies
Fast and high concentrations
Slow and low concentrations

9. Extracellular Signals
Protein Modification can be fast
Gene Expression can be slow

10. Signal Sharing Water-soluble (hydrophilic) Molecules
Gap Junctions are short cytoplasmic bridges
Communication is bidirectional

11. Multiple Extracellular Signals
Cells display a particular set of receptors
that responds to another set of signal molecules
Different combinations will result in different functions

12. Same Signal – Different Result
Same signal and same receptor
Differences in intracellular signaling proteins activated
Extracellular signal has no information

13. Signal Gradients Development
Different Level of Receptor Activation lead to different concentrations of regulatory proteins and therefore different gene expression
High Signal Concentration,
One Effect
Low Signal Concentration,
Different Effect

14. Protein Turnover Decrease in Synthesis Results in Degradation
Blue = molecule half life
Applies to proteins within or outside the cell

15. Protein Turnover Increase in Synthesis New molecules being produced
Blue = molecule half life
Another method is conversion of molecules from an inactive to active state

16. Extracellular Signal Molecule Binding
Hydrophilic molecules bind at the cell surface
Hydrophobic and small molecules mass bind in the cell interior

17. Intracellular Receptors
Nitric Oxide
-Produced by Nitric oxide synthase
-Involved in relaxation of smooth
muscle

18. Nitric Oxide -Synthesized from deamination of arginine
-Rapidly diffuses out and into cells to act locally
-Very short half life, 5-10 seconds
-Reversibly binds to the active site of guanylyl cyclase to produce cyclic GMP
-Guanylyl cyclase acts as both the intracellular receptor and as the intracellular signaling protein
-Phophodiesterase rapidly degrades cGMP back to GMP

19. Nitric Oxide Synthases (NOS)
Types:
eNOS – epithelial NOS
-activated by calcium and phosphorylation
nNOS – nerve and muscle NOS
-constitutively make NOS
-activated by calcium influx
iNOS – macrophages
-inducible NOS
-only made when the cell is activated in response
to infection

20. Hydrophobic Signal Molecules
-Diffuse across the plasma membrane
-Bind to intracellular receptor proteins that can then bind to DNA to regulate transcription of specific genes

21. Nuclear Receptor Superfamily
Serve 2 functions:
-Intracellular Receptors
-Intracellular Effectors
-48 human nuclear receptors
-The binding ligand is not known for half of them

22. Inactive Receptors -Found in either the cytosol or the Nucleus
-Inhibitory proteins are typically bound to prevent unwanted transcription

23. Active Receptors
-Ligand binding alters receptor shape and allows binding of additional activator proteins
-They bind as homodimers or heterodimers

24. Conformational Change
The change in receptor shape causes DNA binding resulting in either transcription activation or repression
Translocation to the Nucleus!!!

25. Hormone Response
Negative Feedback
30 minutes
Other gene regulatory proteins are required to combine with the activated receptor to regulate transcription

26. Classes of Cell-Surface Receptors
-Most molecules bind receptors on the target cell surface and do not enter the cell
-Receptors act as a signal transducer
3 Largest Classes:
Ion-Channel-Coupled Receptor
G-Protein-Coupled Receptor
Enzyme-Coupled Receptor

27. Ion-Channel-Coupled Receptors
aka transmitter-gated ion channels
Rapid synaptic signaling between nerve cells, and nerve and muscle cells
Neurotransmitters open and close the ion channels

28. G-Protein-Coupled Receptors
G-Proteins (Trimeric GTP-binding protein) act as an intermediate between the receptor and target protein
Target proteins are enzymes or ion channel
G-Protein Receptors are multipass transmembrane proteins

29. Enzyme-Coupled Receptors
Function in 2 ways:
Directly as enzymes
Associate with enzymes they activate
Typically single-pass transmembrane proteins
Heterogeneous in their structure, but many have kinases activity

30. Intracellular Signaling
Small intracellular mediators or second messengers
-Generated in large numbers after
ligand/receptor binding
-Diffuse away from their source to spread
their signal
-They pass the signal to selected signaling
proteins or effector proteins

31. Signal Transduction