1. Colon cancer is the second leading cause of cancer deaths
in the U.S.
Polyps, the first stage
In tumor development

2. One gene mutated in the progression to malignancy is K-ras
Lodish
et al.
Fig. 24-6

3. This can be visualized in culture
Oncogenes relieve
contact inhibition.
This can be visualized in culture
by “focus formation”
Transfect with H-ras
Transfect with H-ras (close-up)
J Biol Chem : Fiordalisi et al.
J Virol : Yoshioka et al.

4. Isolation of
the first
oncogene
Lodish et al. Fig. 24-4

5. Lipid modification of ras helps target it to the plasma membrane

6. Farnesyltransferase inhibitors
offer a way of reducing ras activity

7. Farnesyltransferase inhibitors offer a way of reducing ras activity
or lonafarnib
Phase II trials:
Leukemias (esp. AML/CML): Initial results promising
(also Advanced Multiple Myeloma)
Urothelial tract (with gemcitabine): in progress
Pancreatic cancer (with gemcitabine): no improvement
Colorectal cancer (with Irinotecan): just beginning
Small cell lung cancer (with Taxol): Discontinued.

8. Ras encodes a GTPase that is active when bound to GTP
Lodish et al. Fig. 20-5

9. Oncogenic Ras is stuck in the GTP-bound state
Ras G12V
Lodish et al. Fig. 20-5

10. The activity of Ras is regulated by
GEFs and GAPs
Lodish et al. Fig

11. Ligand binding activates RTKs
by dimerization
Lodish et al. Fig

12. The RTK-ras pathway: Part 1
Lodish et al. Fig

13. SH2 domains allow “effector” proteins to bind activated receptors
Alberts et al. Fig

14. The RTK-ras pathway: Part 2
Lodish et al. Fig

15. Ras activation triggers a kinase cascade
Lodish et al. Fig

16. RTK signaling ultimately leads to activation of a transcription factor
Gilbert Fig. 6.14

17. The eye of a fly: Key to learning how Ras and RTKs work
Lodish et al. Fig

18. Did you say flies?

19. Did you say flies?

20. This is all I need to know

21. But wait--flies provided the
Key to learning how
Ras and RTKs work
Lodish et al. Fig

22. Each ommatidium is built by a series of cell-cell
interactions

23. Sevenless is required to specify the R7 photoreceptor
Wild-type
sevenless mutant
Lodish et al. Fig

24. Sevenless encodes an RTK
Lodish et al. Fig

25. Looking for other players
in the pathway
using genetics
R7 present
sev pathway activity
sev threshhold
R7 absent
wild type sev sevts sevts sevts; enh*/+
22.7o C o C o C
Lecture slides of Gian Garriga, UC Berkeley

26. A number of genes
were found
that might function
in the RTK pathway

27. A number of genes were found that might function in the RTK pathway
Sos
Ras

28. Ras acts downstream of the RTK Sevenless
Lodish et al. Fig

29. The signal transduction pathway
should look familiar
Alberts et al. Fig

30. Flies were bad enough,
but worms!?

31. Hermaphrodites do it
by themselves

32. Cell ablations demonstrate that a signal
From the anchor cell induces the vulva
Alberts et al. Fig

34. How can we figure out
how to build a vulva?

35. How can we figure out how to build a vulva? GENETICS!
Vul = “bag of worms”
Normal vulva”
Muv

37. The first two vul mutations
identify
the anchor cell signal
and its receptor
Alberts et al. Fig

38. How can we figure out more about how to build a vulva? MORE GENETICS!
Vul = “bag of worms”
Normal vulva”
Muv

39. The vul mutations define
the RTK-Ras pathway
Alberts et al. Fig

40. Parallels in the RTK/ras pathways of humans, flies and worms

41. The RTK-Ras pathway offers drug targets for cancer treatment
e.g., the Raf kinase inhibitor sorafenib
(also inhibits the RTKs VEGFR, PDGFR, and Kit)
Approved for treatment of
advanced renal cell carcinoma (Jan. 2006)
Increased survival in Phase III liver cancer trial
and approved for inoperable form (Nov. 2007)
In clinical trials for melanoma and lung cancer
Alberts et al. Fig