1. Peyton Rous discovered a virus that causes cancer in chickens
No thank you!
Peyton Rous discovered
a virus that causes
cancer in chickens

2. Retroviruses can cause cancer by picking up
mutated versions of normal cellular genes
Alberts et al. Fig

3. The paper
that created
two Nobel laureates
and founded the
modern field of
Cancer biology

4. Retroviruses can also cause cancer by inserting next to and thus
activating the expression of proto-oncogenes
Retroviral insertion
sites in different tumors
Transcribe to mRNA
5 kilobases
exons
wnt-1 gene
Alberts et al. Fig

5. Two mechanisms of gene activation by retroviral insertion
Lodish et al. Fig

6. Protein kinases and protein phosphatases
add and remove phosphate groups from
target proteins
Lodish et al. Fig. 20-5

7. The structures of c-src and v-src
Lodish et al. Fig

8. Src contains three domains that are shared with other proteins
Binds polyproline motifs
Phosphorylates
other proteins
Binds peptides phosphorylated on Tyr

9. Scientists have determined the precise 3-dimensional structure of Src
Xu et al. Nature :

10. Tyrosine phosphorylation of the C-terminus creates an intramolecular
and inhibitory interaction
Lodish et al. Fig

11. Src is normally inactive due to intramolecular inhibition
Lodish et al. Fig

12. has multiple consequences
Activation of Src
has multiple consequences
From Schwartzenberg, Oncogene 17, (1998)

13. Recent work has provided a more detailed model of Src activation
Cowen-Jacob et al. Structure 13, (2005)

14. Recent work has provided a more detailed model of Src activation
Closed = OFF
Open = ON
Cowen-Jacob et al. Structure 13, (2005)

15. Deletion of the C-terminal region leads to activation of v-Src
Lodish et al. Fig

16. Src modulates both cell-cell and cell matrix adhesion: The basics
junctions
Cell-matrix junctions
Basal lamina

17. Src modulates both cell-cell and cell matrix adhesion: The basics
Lodish et al. Fig. 22-2

18. Epithelial cells secrete a special ECM called the basal lamina
Alberts et al. Fig

19. Cells interact with the ECM via Focal adhesions, which also anchor
the actin cytoskeleton
Focal
Adhesions
(orange)
Actin: Green
Alberts et al. Fig

20. Focal adhesions are linked to the actin cytoskeleton Alberts et al.
Fig

21. the focal adhesion to actin and regulates actin polymerization
A complex network
of proteins links
the focal adhesion to actin
and regulates
actin polymerization
Alberts et al.
Fig

22. Focal adhesions are sites of intense protein tyrosine phosphorylation
Actin: Green
Phosphotyrosine: Red

23. An oversimplified model of Src function
Normal skin cell tightly adherent to ECM
Wounding->platelet recruitment->
cell migration and proliferation
Alberts et al.

24. A less oversimplified model
Migratory growth factors
e.g., EGF, PDGF
Extracellular matrix
Src
RTKs
Integrins
FAK
PI-3-
kinase
Adaptors
Actin
Remodel cell-matrix
junctions -> cell motility
From Jones et al. Eur J. Cancer
36, (2000)

25. If Src is a critical regulator of cell adhesion, what happens to
an animal without any Src?
Cell :
Targeted disruption of
the c-src proto-oncogene
leads to osteopetrosis in mice.
Soriano P, Montgomery C,
Geske R, Bradley A.

26. Src has two close relatives:
Why is this phenotype so modest?
Redundancy!!
Src has two close relatives:
Fyn and Yes

27. Different Src family kinases work downstream of different receptors
Alberts et al. Fig

28. Fyn mutant mice are viable but
have defects in myelination of brain neurons
Yes mutant mice are viable but
with subtle changes in B-cell function

29. Src; Fyn; Yes triple mutant mice die
at embryonic day 9.5 with multiple defects
Triple mutant
Wild-type

30. However, triple mutant cells still make focal adhesions
but their motility isimpaired

31. Scientists have determined the precise 3-dimensional structure of Src
Active
site

32. Scientists have determined the precise 3-dimensional structure of Src
Active
site
SU6656

33. In leukemia, adding Src inhibition
to inhibition of the related kinase Abl
improves prognosis in phase II trials
and helps get around drug resistance
dasatinib
Ottmann et al. Blood 110, 2309 (2007)

34. Another Src inhibitor is in Phase I/II trials
for metastatic pancreatic cancer
Active
site
AZD0530