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What is Signal Transduction? Signal Transduction is the process by which a cell

CZ5211 Topics in Computational Biology Lecture 8: Biological Pathways III: Signaling Pathways Prof. Chen Yu Zong Tel: 6874-6877 Email: yzchen@cz3.nus.edu.sg http://xin.cz3.nus.edu.sg Room 07-24, level 7, SOC1, NUS. What is Signal Transduction?

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What is Signal Transduction? Signal Transduction is the process by which a cell

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  1. CZ5211 Topics in Computational BiologyLecture 8: Biological Pathways III: Signaling PathwaysProf. Chen Yu ZongTel: 6874-6877Email: yzchen@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 Cell’s 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

  11. Growth Factor Receptors

  12. Most growth factors bind Receptor Tyrosine Kinases

  13. C ha r a c te r isti c s of the C o m mon C l a ss e s of R T K s C l ass Ex a m p les S tr uc t u r al Fe a tu r es o f C l ass E GF r e c ept o r, I cys te i n e -r ic h se quen ces NE U / H ER 2, HER 3 i n s u li n r e c ept o r, cys te i n e -r ic h se quen ces ; c ha r a c ter ize d b y II IG F -1 r e c ept o r d is u l f i d e - li n k ed h eter o tetr a mer s PD GF r e c epto rs , c ont ai n 5 i m m uno g l o bu li n- lik e d oma i n s; III c - Ki t c ont ai n the kin a s e i n s e r t c ont ai n 3 i m m uno g l o bu li n- lik e d oma i n s a s I V F G F r ec epto rs w e ll a s t h e ki na s e ins ert; ac i dic dom ai n v a sc u l a r en d othe li a l c e ll c ont ai n 7 i m m uno g l o bu li n- lik e d oma i n s a s V w e ll a s t h e ki na s e ins ert d o ma i n g r o w th fa c t o r ( VE GF ) re c e p tor het e rod im er ic lik e t h e cl a ss II r e c ept o r s he p ato cy te g ro w th e xc e p t that one of the t w o prot e i n s ubun i t s fa c t o r ( H G F ) a nd V I is c o m p l ete ly e x t r a c e ll u l a r . Th e H GF sc att e r fa c t o r ( SC ) r ec epto r is a p r oto- o n c oge n e that w as r ec epto rs o r i gi na lly i dent i f i e d a s th e Met o n c oge n e ne u rot r oph i n c ont ai n no o r fe w cys t ei ne- r i ch do m a i n s ; r ec epto r fam ily V II (t rk A , tr kB , tr kC) N GF R h a s l eu ci n e r ic h d o ma i n an d N GF r e c epto r

  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 cell’s 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 TGF-a GM-CSF

  19. Induction of cancer by alternations in several types of proteins involved in cell growth control

  20. Generic SignalTransduction

  21. RTK SignalTransduction

  22. 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)

  23. Mechanisms for Activation of Signaling Proteins by RTKs Activation by membrane translocation Activation by a conformational change Activation by tyrosine phosphorylation

  24. 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

  25. Activation of MAPK Pathways by Multiple Signals Growth, differentiation, inflammation, apoptosis -> tumorigenesis

  26. Overview of MAPK Signaling Pathways

  27. The MAPK Pathway Activated by RTK

  28. P RTK ST- PI3K pathway

  29. Apoptosis Pathways

  30. TGF Pathway

  31. 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

  32. Ras recruits Raf to the membrane

  33. Activation Pathways for c-Src

  34. ST intermediates can be targets for anti-cancer drugs Kinases: Raf

  35. ST intermediates can be targets for anti-cancer drugs Kinases: Bcr-Abl

  36. On-Line Resources Mechanisms of Signal Transduction http://www-isu.indstate.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/PathwayGeneSearch.asp?geneValue=g Comprehensive illustrations of signaling pathways Extracellular Signal Molecules http://www.grt.kyushu-u.ac.jp/spad/menu.html Signals and the pathways stimulated by each Kinetic constants http://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.

  37. On-Line Resources 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/tumorbio/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

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