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Signal Transduction and Cancer
Lecture I: Growth Factors and ReceptorsOutline:A) What is Signal Transduction?B) What are Growth Factors?C) How do they contribute to normal ST?D) How is this ST deregulated in Cancer?
Lecture I: Growth Factors and ReceptorsWhat is Signal Transduction?
Signal Transduction is the process by which a cell converts an extracellular signal into a response.
Involved in:Cell-cell communication
Cell’s response to environment
Intracellular homeostatsis- internal communication
Generic Signalling Pathway
Signal
Receptor (sensor)
Transduction Cascade
Targets
Response
Altered Metabolism
MetabolicEnzyme
Gene Regulator Cytoskeletal Protein
Altered Gene
Expression
Altered Cell Shape or Motility
Adapted from Molecular Biology of the Cell,(2002), 4th edition, Alberts et al.
Components of SignallingWhat 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 = LIGANDLigand- A molecule that binds to a specific site on another molecule, usually a protein, ie receptor
Components of SignallingWhat are Receptors?Sensors, what the signal/ligand binds to initiate ST
Cell surface
Intracellular
Hydrophillic LigandCell-Surface Receptor
Plasma membrane
Hydrophobic Ligand
Carrier Protein
IntracellularReceptor
Nucleus
Adapted from Molecular Biology of the Cell,(2002), 4th edition, Alberts et al.
Cell Surface Receptor Types:
1) Ligand-gated ion channel
Cell Surface Receptor Types:
2) G-Protein Coupled Receptor
Cell Surface Receptor Types:
3) Enzyme-linked Receptor eg Growth Factor Receptors
Growth FactorsLigands which bind enzyme linked receptorsSignal diverse cellular responses including:ProliferationDifferentiationGrowthSurvival Angiogenesis
Can signal to multiple cell types or be specific
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
Growth Factors
Growth Factor Receptors
Most growth factors bind Receptor Tyrosine Kinases
Characteristics of the Common Classes ofRTKs
Class Examples Structural Features of Class
IEGF receptor,NEU/HER2, HER3
cysteine-rich sequences
IIinsulin receptor,IGF-1 receptor
cysteine-rich sequences; characterized bydisulfide-linked heterotetramers
IIIPDGF receptors,c-Kit
contain 5 immunoglobulin-like domains;contain the kinase insert
IV FGF receptorscontain 3 immunoglobulin-like domains aswell as the kinase insert; acidic domain
V
vascularendothelial cellgrowth factor(VEGF) receptor
contain 7 immunoglobulin-like domains aswell as the kinase insert domain
VI
hepatocyte growthfactor (HGF) andscatter factor (SC)receptors
heterodimeric like the class II receptorsexcept that one of the two protein subunitsis completely extracellular. The HGFreceptor is a proto-oncogene that wasoriginally identified as the Met oncogene
VII
neurotrophinreceptor family(trkA, trkB, trkC)and NGF receptor
contain no or few cysteine-rich domains;NGFR has leucine rich domain
Growth Factor Receptor Activation IRTK RS/TK
Growth Factor Receptor Activation II
Growth signal autonomy,Insensitivity to anti-growth signals,Resistance to apoptosis:Uncouple cell’s growth program from signals in the environment.
Growth factors in normal cells serveas environmental signals.
Growth Factor ST and Cancer
Growth factors regulate growth, proliferation, and survival.These are all deregulated in cancer.
Hanahan and Weinberg, (2000) Hallmarks of Cancer, Cell (100) 57
Growth factors with Oncogenic PotentialPDGF, 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 NGFB chain (c-sis) BDNF
FGF Family NT3acidic FGF Cytokines (Hematopoietic)basic FGF IL-2
EGF Family IL-3EGF M-CSFTGF-a GM-CSF
GF Receptors with Oncogenic PotentialEGFR, kinase activity stimulated by EGF-1 and TGF-a involved incell 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 FamilyCSF-1R (c-fms)SLF R (c-kit)
Induction of cancer by alternations in several types of proteins involved in cell growth control
Signal Transduction and Cancer
Lecture II: Intracellular SignallingOutline:A) What are some signalling pathways?B) What are their cell biological outputs?C) How do these result in the cancer phenotype?D) How can we exploit signalling pathways for therapy?
Generic Signal Transduction
RTK Signal Transduction
Signal TransductionDownstream effectors
Protein Signaling Modules (Domains)
SH2 and PTB bind to tyrosine phosphorylated sitesSH3 and WW bind to proline-rich sequencesPDZ domains bind to hydrophobic residues at the C-termini of target proteinsPH domains bind to different phosphoinositidesFYVE domains specifically bind to Pdtlns(3)P (phosphatidylinositol 3-phosphate)
Mechanisms for Activation of Signaling Proteins by RTKs
Activation by membrane translocation
Activation by a conformational change
Activation by tyrosine phosphorylation
Mechanisms for Attenuation & Termination of RTK Activation
1) Ligand antagonists2) Receptor antagonists3) Phosphorylation and dephosphorylation4) Receptor endocytosis5) Receptor degradation by the ubiquitin-proteosome pathway
Activation of MAPK Pathways by Multiple Signals
Growth, differentiation, inflammation, apoptosis -> tumorigenesis
Overview of MAPK Signaling Pathways
The MAPK Pathway Activated by RTK
P
RTK ST- PI3K pathway
Proto-oncogenes that Encode for Signalling Proteins
Serine/Threonine Kinasesc-raf familyakt
Non-receptor Tyrosine Kinasessrcabl
Receptor associated binding proteinsc-ras family
Ras recruits Raf to the membrane
The prototypic TK oncogene is bcr/abl. The bcr/abl fusiononcogene i s formed when the c-abl TK gene onchromosome 9 is translocated to chromosome 22 and fusedwith part of the bcr gene on that chromosome. The resultinghybrid chromosome, the Philadelphia chromosome, encodesa new protein called Bcr/Abl. New protein has increasedkinase activity and drives proliferation causingtransformation. Charatceristic of CML a nd some forms ofALL.
C-abl: Tyrosine Kinase activation by Translocation
ST intermediates can be targets for anti-cancer drugs
Kinases:Raf
ST intermediates can be targets for anti-cancer drugs
Kinases:Bcr-Abl
Growth Factor Receptors can be drug targets