CZ5211 Topics in Computational Biology Lecture 8: Biological Pathways III: Signaling Pathways Prof. Chen Yu Zong Tel: [phone] Email: [e-mail] http://xin.cz3.nus.edu.sg Room 07-24, level 7, SOC1, NUS

1
CZ5211 Topics in Computational Biology Lecture
8 Biological Pathways III Signaling
PathwaysProf. Chen Yu ZongTel
6874-6877Email yzchen_at_cz3.nus.edu.sghttp//xin.
cz3.nus.edu.sgRoom 07-24, level 7, SOC1, NUS
2
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 Signaling 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 Signaling
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 Signaling
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
• Signaling diverse cellular responses including
• Proliferation
• Differentiation
• Growth
• Survival
• Angiogenesis
• Capable of sending signal to multiple cell types
  or be specific

10
Growth Factors
Factor Principal Source Primary Activity Comments
PDGF platelets, endothelial cells, placenta promotes proliferation of connective tissue, glial and smooth muscle cells two different protein chains form 3 distinct dimer forms AA, AB and BB
EGF submaxillary gland, Brunners gland promotes proliferation of mesenchymal, glial and epithelial cells  
TGF-? common in transformed cells may be important for normal wound healing related to EGF
FGF wide range of cells protein is associated with the ECM promotes proliferation of many cells inhibits some stem cells induces mesoderm to form in early embryos at least 19 family members, 4 distinct receptors
NGF   promotes neurite outgrowth and neural cell survival several related proteins first identified as proto-oncogenes trkA (trackA), trkB, trkC
Erythropoietin kidney promotes proliferation and differentiation of erythrocytes  
TGF-? activated TH1 cells (T-helper) and natural killer (NK) cells anti-inflammatory (suppresses cytokine production and class II MHC expression), promotes wound healing, inhibits macrophage and lymphocyte proliferation at least 100 different family members
IGF-I primarily liver promotes proliferation of many cell types related to IGF-II and proinsulin, also called Somatomedin C
IGF-II variety of cells promotes proliferation of many cell types primarily of fetal origin related to IGF-I and proinsulin
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
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)
18
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 over-expressed 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
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
(No Transcript)
25
(No Transcript)
26
Generic Signal Transduction
27
RTK Signal Transduction
28
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)
29
Mechanisms for Activation of Signaling Proteins
by RTKs
Activation by membrane translocation
Activation by a conformational change
Activation by tyrosine phosphorylation
30
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
31
Activation of MAPK Pathways by Multiple Signals
Growth, differentiation, inflammation, apoptosis
-gt tumorigenesis
32
Overview of MAPK Signaling Pathways
33
The MAPK Pathway Activated by RTK
34
P
RTK ST- PI3K pathway
35
Apoptosis Pathways
36
TGF Pathway
37
Proto-Oncogenes that Encode for Signaling
Proteins
Serine/Threonine Kinases c-raf
family akt Non-receptor Tyrosine
Kinases src abl Receptor associated binding
proteins c-ras family
38
(No Transcript)
39
(No Transcript)
40
Ras recruits Raf to the membrane
41
Activation Pathways for c-Src
42
(No Transcript)
43
ST intermediates can be targets for anti-cancer
drugs
Kinases Raf
44
ST intermediates can be targets for anti-cancer
drugs
Kinases Bcr-Abl
45
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.genome.ad.jp/kegg/kegg4.html
KEGG Kyoto Encyclopedia of Genes and Genomes.
Site contains Pathway Info, Disease Catalogs,
Cell Catalogs, Molecule Catalog, and Genomic
Info. It also provides Links to Pathway and Other
Databases. http//www.biocarta.com/genes/Pathway
GeneSearch.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 Kinetic
constants http//bidd.nus.edu.sg/group/kdbi/kdbi.a
sp Kinetic Data of Biomolecular Interactions, a
collection of experimentally determined kinetic
data of protein-protein, protein-RNA,
protein-DNA, protein-ligand, RNA-ligand,
DNA-ligandbinding or reaction events described in
the literature.
46
On-Line Resources
Mammalian MAPK signalling pathways http//kinase.o
ci.utoronto.ca/signallingmap.html MAPK signaling
pathway, with information on each component
Small Molecule Platform http//www.onyx-pharm.co
m/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