CZ5225: Modeling and Simulation in Biology Lecture 10: Biological Pathways II: Signaling Pathways...
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Transcript of CZ5225: Modeling and Simulation in Biology Lecture 10: Biological Pathways II: Signaling Pathways...
CZ5225: Modeling and Simulation in BiologyCZ5225: Modeling and Simulation in Biology
Lecture 10: Biological Pathways II: Lecture 10: Biological Pathways II: Signaling PathwaysSignaling Pathways
Prof. Chen Yu ZongProf. Chen Yu Zong
Tel: 6874-6877Tel: 6874-6877Email: Email: [email protected]@cz3.nus.edu.sg
http://xin.cz3.nus.edu.sghttp://xin.cz3.nus.edu.sgRoom 07-24, level 7, SOC1, NUSRoom 07-24, level 7, SOC1, NUS
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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
Cell’s response to environment
Intracellular homeostasis- internal communication
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Generic Signaling PathwayGeneric Signaling PathwaySignal
Receptor (sensor)
Transduction Cascade
Targets
Response Altered
Metabolism
MetabolicEnzyme
Gene Regulator Cytoskeletal Protein
Altered Gene
Expression
Altered Cell Shape or Motility
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Components of SignalingWhat 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
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Components of SignalingWhat 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
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Cell Surface Receptor Types:
1) Ligand-gated ion channel
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Cell Surface Receptor Types:
2) G-Protein Coupled Receptor
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Cell Surface Receptor Types:
3) Enzyme-linked Receptor eg Growth Factor Receptors
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Growth Factors
Ligands which bind enzyme linked receptorsSignaling diverse cellular responses including:
• Proliferation• Differentiation• Growth• Survival • Angiogenesis
Capable of sending signal to multiple cell types or be specific
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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
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Growth Factor Receptors
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Most growth factors bind Receptor Tyrosine Kinases
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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
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neurotrophinreceptor family(trkA, trkB, trkC)and NGF receptor
contain no or few cysteine-rich domains;NGFR has leucine rich domain
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Growth Factor Receptor Activation IRTK RS/TK
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Growth Factor Receptor Activation II
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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.
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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 familyerbB1 (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)
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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 over-expressed in cancer such as TGF-a. Autocrine signalling leads to deregulated growth.
PDGF family NeurotrophinsA 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
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2020
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Induction of cancer by alternations in several types of proteins involved in cell growth control
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Generic Signal Transduction
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RTK Signal Transduction
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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)
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Mechanisms for Activation of Signaling Proteins by RTKs
Activation by membrane translocation
Activation by a conformational change
Activation by tyrosine phosphorylation
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Mechanisms for Attenuation & Termination of RTK Activation
1) Ligand antagonists2) Receptor antagonists3) Phosphorylation and dephosphorylation4) Receptor endocytosis5) Receptor degradation by the ubiquitin-proteosome pathway
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Activation of MAPK Pathways by Multiple Signals
Growth, differentiation, inflammation, apoptosis -> tumorigenesis
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Overview of MAPK Signaling Pathways
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The MAPK Pathway Activated by RTK
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RTK ST- PI3K pathway
P
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Apoptosis Pathways
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TGF Pathway
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Proto-Oncogenes that Encode for Signaling Proteins
Serine/Threonine Kinasesc-raf familyakt
Non-receptor Tyrosine Kinasessrcabl
Receptor associated binding proteinsc-ras family
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3838
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Ras recruits Raf to the membraneRas recruits Raf to the membrane
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Activation Pathways for c-SrcActivation Pathways for c-Src
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ST intermediates can be targets for anti-cancer drugs
Kinases:Raf
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ST intermediates can be targets for anti-cancer drugs
Kinases:Bcr-Abl
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On-Line ResourcesMechanisms of Signal Transductionhttp://www-isu.indstate.edu/thcme/mwking/signal-transduction.html Clear, illustrated summaries of the various mechanisms of signal transduction
Pathwayshttp://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/PathwayGeneSearch.asp?geneValue=g Comprehensive illustrations of signaling pathways
Extracellular Signal Moleculeshttp://www.grt.kyushu-u.ac.jp/spad/menu.html Signals and the pathways stimulated by each
Kinetic constantshttp://bidd.nus.edu.sg/group/kdbi/kdbi.asp 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.
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On-Line Resources
Viruses and Cancerhttp://www.geocities.com/tumorbio/vir/vir.htm History and current summary of viruses and human cancer
Science Maagazine Signal Tansduction Knowledge Environment-Pathwayshttp://stke.sciencemag.org/cm/index.dtl
Mammalian MAPK signalling pathwayshttp://kinase.oci.utoronto.ca/signallingmap.html MAPK signaling pathway, with information on each component
Small Molecule Platformhttp://www.onyx-pharm.com/onyxtech/small_molecule_platform.html The development of anti-cancer drugs that act on the ras signaling pathway
Signal Transductionhttp://www.kumc.edu/biochemistry/bioc800/siglofra.htm Signal transduction from a medical viewpoint