Signal Transduction and Cancer

1
Signal Transduction and Cancer

• Lecture I Growth Factors and Receptors
• Outline
• What is Signal Transduction?
• What are Growth Factors?
• How do they contribute to normal ST?
• How is this ST deregulated in Cancer?

2
Lecture I Growth Factors and Receptors What is
Signal Transduction? Signal Transduction is the
process by which a cell converts an
extracellular signal into a response. Involved
in Cell-cell communication Cells response to
environment Intracellular homeostatsis- internal
communication
3
Generic Signalling Pathway
Signal Receptor (sensor) Transduction
Cascade Targets Response
Metabolic Enzyme
Cytoskeletal Protein
Gene Regulator
Altered Metabolism
Altered Gene Expression
Altered Cell Shape or Motility
Adapted from Molecular Biology of the
Cell,(2002), 4th edition, Alberts et al.
4
Components of Signalling
What can be the Signal? External message to the
cell

• Peptides / Proteins- Growth Factors
• Amino acid derivatives - epinephrine, histamine
• Other small biomolecules - ATP
• Steroids, prostaglandins
• Gases - Nitric Oxide (NO)
• Photons
• Damaged DNA
• Odorants, tastants

Signal LIGAND Ligand- A molecule that binds to
a specific site on another molecule, usually a
protein, ie receptor
5
Components of Signalling
What are Receptors? Sensors, what the
signal/ligand binds to initiate ST
Hydrophillic Ligand
Cell-Surface Receptor
Cell surface Intracellular
Plasma membrane
Hydrophobic Ligand
Carrier Protein
Intracellular Receptor
Nucleus
Adapted from Molecular Biology of the
Cell,(2002), 4th edition, Alberts et al.
6

• Cell Surface Receptor Types
• Ligand-gated ion channel

7

• Cell Surface Receptor Types
• 2) G-Protein Coupled Receptor

8

• Cell Surface Receptor Types
• 3) Enzyme-linked Receptor
• eg Growth Factor Receptors

9
Growth Factors
Ligands which bind enzyme linked receptors Signal
diverse cellular responses including Proliferatio
n Differentiation Growth Survival
Angiogenesis Can signal to multiple cell types
or be specific
10
Growth Factors
11
Growth Factor Receptors
12
Most growth factors bind Receptor Tyrosine Kinases
13
(No Transcript)
14
Growth Factor Receptor Activation I
RTK
RS/TK
15
Growth Factor Receptor Activation II
16
Growth Factor ST and Cancer
Growth signal autonomy, Insensitivity to
anti-growth signals, Resistance to
apoptosis Uncouple cells growth program from
signals in the environment. Growth factors in
normal cells serve as environmental signals.
Hanahan and Weinberg, (2000) Hallmarks of Cancer,
Cell (100) 57
Growth factors regulate growth, proliferation,
and survival. These are all deregulated in cancer.
17
Growth factors with Oncogenic Potential
PDGF, originally shown to regulate proliferation,
was also shown to have homology to v-sis, the
simian sarcoma virus. Other viral oncogenes
encoded protein products that were growth factors
that often overexpressed in cancer such as TGF-a.
Autocrine signalling leads to deregulated
growth.
PDGF family Neurotrophins A chain NGF B
chain (c-sis) BDNF FGF Family NT3 acidic
FGF Cytokines (Hematopoietic) basic
FGF IL-2 EGF Family IL-3 EGF M-CSF TG
F-a GM-CSF
18
GF Receptors with Oncogenic Potential
EGFR, kinase activity stimulated by EGF-1 and
TGF-a involved in cell growth and
differentiation, was linked via sequence
homology to a known avian erythroblastosis virus
onocgene, v-erbB. Since then, many oncogenes have
been shown to encode for GFRs.
EGFR family Insulin Receptor family erbB1
(c-erbB) IGF-1 (c-ros) erbB2 (neu)
Neurotrophins FGF Family NGFR (trk)
FGFR-1(fig) BDNFR (trk-B) FGFR-2(K-sam) NT3
R (trk-C) PDGFR Family CSF-1R
(c-fms) SLF R (c-kit)
19
(No Transcript)
20
(No Transcript)
21
(No Transcript)
22
(No Transcript)
23
Induction of cancer by alternations in several
types of proteins involved in cell growth
control
24
Signal Transduction and Cancer

• Lecture II Intracellular Signalling
• Outline
• What are some signalling pathways?
• What are their cell biological outputs?
• How do these result in the cancer phenotype?
• How can we exploit signalling pathways for
  therapy?

25
Generic Signal Transduction
26
RTK Signal Transduction
27
Signal Transduction Downstream effectors
Protein Signaling Modules (Domains)
SH2 and PTB bind to tyrosine phosphorylated
sites SH3 and WW bind to proline-rich
sequences PDZ domains bind to hydrophobic
residues at the C-termini of target proteins PH
domains bind to different phosphoinositides FYVE
domains specifically bind to Pdtlns(3)P
(phosphatidylinositol 3-phosphate)
28
Mechanisms for Activation of Signaling Proteins
by RTKs
Activation by membrane translocation
Activation by a conformational change
Activation by tyrosine phosphorylation
29
Mechanisms for Attenuation Termination of RTK
Activation
1) Ligand antagonists 2) Receptor antagonists 3)
Phosphorylation and dephosphorylation 4) Receptor
endocytosis 5) Receptor degradation by the
ubiquitin-proteosome pathway
30
Activation of MAPK Pathways by Multiple Signals
Growth, differentiation, inflammation, apoptosis
-gt tumorigenesis
31
Overview of MAPK Signaling Pathways
32
The MAPK Pathway Activated by RTK
33
RTK ST- PI3K pathway
P
34
(No Transcript)
35
(No Transcript)
36
Proto-oncogenes that Encode for Signalling
Proteins
Serine/Threonine Kinases c-raf
family akt Non-receptor Tyrosine
Kinases src abl Receptor associated binding
proteins c-ras family
37
(No Transcript)
38
(No Transcript)
39
(No Transcript)
40
Ras recruits Raf to the membrane
41
(No Transcript)
42
(No Transcript)
43
(No Transcript)
44
(No Transcript)
45
(No Transcript)
46
(No Transcript)
47
C-abl Tyrosine Kinase activation by Translocation
48
ST intermediates can be targets for anti-cancer
drugs
Kinases Raf
49
ST intermediates can be targets for anti-cancer
drugs
Kinases Bcr-Abl
50
Growth Factor Receptors can be drug targets
51
(No Transcript)
52
On-Line Resources
Mechanisms of Signal Transduction http//www-isu.i
ndstate.edu/thcme/mwking/signal-transduction.html
Clear, illustrated summaries of the various
mechanisms of signal transduction
Pathways http//www.biocarta.com/genes/PathwayGe
neSearch.asp?geneValueg Comprehensive
illustrations of signaling pathways
Extracellular Signal Molecules http//www.grt.ky
ushu-u.ac.jp/spad/menu.html Signals and the
pathways stimulated by each Mammalian MAPK
signalling pathways http//kinase.oci.utoronto.ca/
signallingmap.html MAPK signaling pathway, with
information on each component Small Molecule
Platform http//www.onyx-pharm.com/onyxtech/small_
molecule_platform.html The development of
anti-cancer drugs that act on the ras signaling
pathway Signal Transduction http//www.kumc.edu/
biochemistry/bioc800/siglofra.htm Signal
transduction from a medical viewpoint
Viruses and Cancer http//www.geocities.com/tumorb
io/vir/vir.htm History and current summary of
viruses and human cancer Science Maagazine
Signal Tansduction Knowledge Environment-Pathways
http//stke.sciencemag.org/cm/index.dtl