Transcript The RTK-ras pathway: Part 1

Colon cancer is the second
leading cause of cancer deaths
in the U.S.
Polyps, the first stage
In tumor development
http://www.clevelandclinic.org/registries/inherited/fap.htm
One gene mutated in the progression
to malignancy is K-ras
Lodish
et al.
Fig. 24-6
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 2002 277:10813-23 Fiordalisi et al.
J Virol 2000 74:1008-13 Yoshioka et al.
Isolation of
the first
oncogene
Lodish et al. Fig. 24-4
Lipid modification of ras helps
target it to the plasma membrane
Farnesyltransferase inhibitors
offer a way of reducing ras activity
Farnesyltransferase inhibitors
offer a way of reducing ras activity
R115777
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.
Ras encodes a GTPase
that is active
when bound to GTP
Lodish et al. Fig. 20-5
Oncogenic Ras is
stuck in the
GTP-bound state
Ras G12V
Lodish et al. Fig. 20-5
The activity of Ras is regulated by
GEFs and GAPs
Lodish et al. Fig. 20-22
Ligand binding activates RTKs
by dimerization
Lodish et al. Fig. 20-21
The RTK-ras pathway: Part 1
Lodish et al. Fig. 20-23
SH2 domains allow “effector” proteins
to bind activated receptors
Alberts et al. Fig. 15-49
The RTK-ras pathway: Part 2
Lodish et al. Fig. 20-23
Ras activation
triggers a
kinase
cascade
Lodish et al. Fig. 20-28
RTK signaling ultimately leads to
activation of a transcription factor
Gilbert Fig. 6.14
The eye of a fly:
Key to learning how
Ras and RTKs work
Lodish et al. Fig. 20-24
Did you say flies?
Did you say flies?
This is all I need to know
But wait--flies provided the
Key to learning how
Ras and RTKs work
Lodish et al. Fig. 20-24
Each ommatidium is built
by a series of cell-cell
interactions
Sevenless is required
to specify the R7
photoreceptor
Wild-type
sevenless mutant
Lodish et al. Fig. 20-24
Sevenless encodes an RTK
Lodish et al. Fig. 20-25
Looking for other players
in the pathway
using genetics
R7 present
sev threshhold
R7 absent
wild type sev-
sevts
sevts
22.7o C 24.3o C
sevts; enh*/+
22.7o C
Lecture slides of Gian Garriga, UC Berkeley
A number of genes
were found
that might function
in the RTK pathway
A number of genes
were found
that might function
in the RTK pathway
Sos
Ras
Ras acts downstream of
the RTK Sevenless
Lodish et al. Fig. 20-25
The signal transduction pathway
should look familiar
Alberts et al. Fig. 15-53
Flies were bad enough,
but worms!?
Hermaphrodites do it
by themselves
Cell ablations demonstrate that a signal
From the anchor cell induces the vulva
Alberts et al. Fig. 21-41
How can we figure out
how to build a vulva?
How can we figure out
how to build a vulva?
GENETICS!
Vul = “bag of worms”
Normal vulva”
Muv
The first two vul mutations
identify
the anchor cell signal
and its receptor
Alberts et al. Fig. 21-44
How can we figure out
more about
how to build a vulva?
MORE GENETICS!
Vul = “bag of worms”
Normal vulva”
Muv
The vul mutations define
the RTK-Ras pathway
Alberts et al. Fig. 21-44
Parallels in the RTK/ras pathways
of humans, flies and worms
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. 21-44