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: yzchen@cz3.nus.edu.sgyzchen@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

VII

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