Peyton Rous discovered

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No thank you!
Peyton Rous discovered a virus that causes cancer
in chickens
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Retroviruses can cause cancer by picking
up mutated versions of normal cellular genes
Alberts et al. Fig. 24-23
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The paper that created two Nobel laureates and
founded the modern field of Cancer biology
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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. 22-24
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Two mechanisms of gene activation by retroviral
insertion
Lodish et al. Fig. 24-10
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Protein kinases and protein phosphatases add and
remove phosphate groups from target proteins
Lodish et al. Fig. 20-5
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The structures of c-src and v-src
Lodish et al. Fig. 24-17
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Src contains three domains that are shared with
other proteins
Binds polyproline motifs
Phosphorylates other proteins
Binds peptides phosphorylated on Tyr
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Scientists have determined the precise
3-dimensional structure of Src
Xu et al. Nature. 1997 385595-602
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Tyrosine phosphorylation of the
C-terminus creates an intramolecular and
inhibitory interaction
Lodish et al. Fig. 24-17
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Src is normally inactive due to intramolecular
inhibition
Lodish et al. Fig. 24-17
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Activation of Src has multiple consequences
From Schwartzenberg, Oncogene 17, 1463-1468 (1998)
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Recent work has provided a more detailed model
of Src activation
Cowen-Jacob et al. Structure 13, 861-871 (2005)
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Recent work has provided a more detailed model
of Src activation
Closed OFF
Open ON
Cowen-Jacob et al. Structure 13, 861-871 (2005)
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Deletion of the C-terminal region leads to
activation of v-Src
Lodish et al. Fig. 24-17
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Src modulates both cell-cell and cell matrix
adhesion The basics
Cell-cell junctions
Cell-matrix junctions
Basal lamina
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Src modulates both cell-cell and cell matrix
adhesion The basics
Lodish et al. Fig. 22-2
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Epithelial cells secrete a special ECM called
the basal lamina
Epithelial cells
Basal Lamina
Alberts et al. Fig. 19-54
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Cells interact with the ECM via Focal adhesions,
which also anchor the actin cytoskeleton
Focal Adhesions (orange)
Actin Green
Alberts et al. Fig. 17-42
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Focal adhesions are linked to the actin
cytoskeleton
Alberts et al. Fig. 16-75
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A complex network of proteins links the focal
adhesion to actin and regulates actin
polymerization
Alberts et al. Fig. 16-75
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Focal adhesions are sites of intense protein
tyrosine phosphorylation
Focal adhesions
Actin Green
Phosphotyrosine Red
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An oversimplified model of Src function
Normal skin cell tightly adherent to ECM
Wounding-gtplatelet recruitment-gt cell migration
and proliferation
Alberts et al.
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A less oversimplified model
Migratory growth factors e.g., EGF, PDGF
Extracellular matrix
Src
Integrins
RTKs
FAK
PI-3- kinase
Adaptors
Actin
Remodel cell-matrix junctions -gt cell motility
From Jones et al. Eur J. Cancer 36, 1595-1606
(2000)
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If Src is a critical regulator of cell adhesion,
what happens to an animal without any Src?
Cell 1991 64693-702 Targeted disruption of
the c-src proto-oncogene leads to osteopetrosis
in mice. Soriano P, Montgomery C, Geske R,
Bradley A.
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Why is this phenotype so modest?
Redundancy!!
Src has two close relatives Fyn and Yes
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Different Src family kinases work downstream of
different receptors
Alberts et al. Fig. 23-54
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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
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Src Fyn Yes triple mutant mice die at
embryonic day 9.5 with multiple defects
Triple mutant
Wild-type
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However, triple mutant cells still make focal
adhesions but their motility isimpaired
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Scientists have determined the precise
3-dimensional structure of Src
Active site
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Scientists have determined the precise
3-dimensional structure of Src
Active site
SU6656
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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)
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Another Src inhibitor is in Phase I/II trials for
metastatic pancreatic cancer
Active site
AZD0530