1. Sustaining Proliferative Signaling and Evading Growth Suppressors
Oct 26, 2017

2. Hallmarks of Cancer, 2011

3. Epidermal Growth Factor Receptor
-EGFR (aka ErbB1 or HER1)
-tyrosine kinase receptor
-3 other family members (HER2, HER3, HER4)
-Binding partners include:
-EGF
-amphiregulin
-neuregulins

4. EGF Signaling Pathway

5. Dimerization of EGFR
-Conformation change upon binding, allowing domain II to interact
-Can form heterodimers with other family members

6. Dimerization of EGFR
-Phosphorylation of each of the Receptors by its partner

7. Signal Termination Multi-step process
Additional phosphorylation, conformation change
Inhibits EGF binding
Dephosphorylation of tyrosine residues
Binging of Negative regulators

8. Translocation of Proteins to EGFR
-EGFR when phosphorylated attracts SH2 domain containing proteins
-SH2 – Src homology 2 domain,
-Binds to phosphorylated tyrosines
-Grb2 – Contains SH2 domain and Binds EGFR-P
-Contains a SH3 domain as well
-SH3 – Src homology 3 domain
-Binds to short proline-rich amino acid sequence
-SOS – Son of Sevenless,
contains the proline-rich
sequence.
-Activates RAS

9. Insulin Receptor Complex

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

11. RAS Activation -RAS – GTP binding protein SOS
GAP – GTPase-activating protein
GEF – Guanine nucleotide exchange factor, SOS
RAS- becomes farnesylated

12. Raf Activation -Activated RAS-GTP recruits Raf to the membrane
-Raf is typically inhibited and RAS-GTP relieves the inhibition
-Activated Raf can then phosphorylate MEK
All kinases
GTP

13. MAPK Activation -Activated MEK phosphorylates MAPK
-Activated MAPK then enters the nucleus to phosphorylate transcription factors than can then alter their binding
GTP

14. Transcription Factors
-MAPK can activate AP-1
-Induces cell cycle progression by activating the Cyclin D gene
-Composed of jun and fos proteins can act as a leucine zipper to Bind to DNA

18. Transcription Factors
AP-1 activity in induced by 2 mechanisms:
1. jun becomes phosphorylated
2. MAPK activity increase sthrough other transcription factors the levels of jun and fos

19. MAPK induces Myc
-MAPK targets several of the Myc family transcription Factors
Myc family includes: Myc, Max, Mad, Mxi
Myc and Max form a heterodimer of a helix-turn-helix leucine zipper
Gene targets include: N-Ras and p53 and bind at the E box
Max and Mad/Mxi heterodimer inhibit Myc and also bind at the E box but repress transcription

21. Mad/Mxi
Myc
Max
Max

23. EGF Signaling Pathway

24. RAS Interacts with PI3K
-Activated RAS brings PI3K to the membrane and converts PIP2 to PIP3
-PIP3 recruits PDK-1 to the membrane

25. Role of PIP3 -PIP3 recruits PDK-1 to the membrane
-PDK-1 phosphorylates Akt

26. Akt Activities
-Activated Akt is involved with anti-apoptotic and survival roles
-mTOR, a kinase involved in promoting anabolic programming such as lipid and nucleotide syntheis

27. Akt Targets

28. EGF Signaling Pathway