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Tyrosine kinases

Tyrosine kinases. http://msbl.helsinki.fi/tkseminar. Biological responses. Activation of Gene expression. Signal trans- duction. Signaling molecules. Producer cell. RNA. Receptor binding. Target cell. proliferation, differentiation, migration, metabolism, etc.

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Tyrosine kinases

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  1. Tyrosine kinases http://msbl.helsinki.fi/tkseminar

  2. Biological responses Activation of Gene expression Signal trans- duction Signaling molecules Producer cell RNA Receptor binding Target cell proliferation, differentiation, migration, metabolism, etc.

  3. Cell surface receptors

  4. Receptor Tyrosine Kinases NH2 ligand binding extracellular transmembrane juxtamembrane ATP tyrosine kinase substrate binding carboxy-terminal tail COOH

  5. VEGF xVEGF-R1

  6. RTK subclasses I II III IV ss ss ss ss EGF-R IGF-1-R VEGF-R3 FGF-R PDGF-Ra

  7. Modular structure of EC domains

  8. RTK ligands • Cytokines (EGF, FGF, CSF-1, insulin) • Membrane-bound proteins (ephrins) • Extracellular matrix components (HSPGs) • Some RTKs need two ligands for activation

  9. Signaling through an RTK

  10. Dimerization or oligomerization • Bivalent ligand • (e.g. VEGF, PDGF) • Ligand-induced conformational change (probably EGF) • Intracomplex conformational change (e.g. insulin)

  11. Transmembrane signal transfer • Exact mechanism unknown • Same or similar mechanism for all RTKs (evidence from hybrid receptors)

  12. Autophosphorylation • Specific Tyr residues, usually outside the • tyrosine kinase domain (juxtamembrane domain, cytoplasmic tail, kinase insert) • Purposes: • - Regulation of tyrosine kinase activity • - Recruitment of signaling molecules

  13. Signaling proteins are modular molecules SH2 PTB SH3 PH/FYVE PZB WW • SH2 (Src-homolgy 2) • PTB (phosphotyrosine binding) • SH3 (Src-homolgy 3) • PH (pleckstrin homology)/FYVE • PDZ • WW

  14. SH2 (Src-homology 2)/PTB (phosphotyrosine binding) • Bind to PY (and sometimes Y) • Specificity is achieved through the context • SH2: 1-6 amino acids C-terminal to PY • PTB: 3-5 amino aids N-terminal to PY (or Y)

  15. SH3 & WW SH3 (Src-homology 3) • Binds to proline motif PXXP WW • Binds to proline motif PXPX

  16. PH/FYVE/PDZ PH (pleckstrin homology)/FYVE • PH domain binds to phosphoinositides (membrane- localization) • FYVE domain binds specifically PtdIns-3-P PDZ (PSD-95, DDLP, ZP1) • Bind to hydrophobic C-terminal strtches of target proteins

  17. Assembly of a specific signaling complex membrane P PTB Enzymatic activity PH/FYVE SH3 WW PDZ SH2 Kinases Phosphatases PLC-g Ras-GAP Rho-GRF P Cellular Targets

  18. Docking proteins Indirect recruitment is the main recruitment method for some receptors (insulin receptor, FGF receptors) Membrane localization Receptor binding Tyrosines Myristyl. PTB FRS2a,b P P P P P Dos PH P P P P P P P TM LAT P P P P P

  19. Topics in activation of effector proteins • Activation by Membrane Translocation • Activation by a Conformational Change • Activation by Tyrosine Phosphorylation

  20. Activation of signaling molecules: PDGF receptor 1. Membrane translocation 2. Conformational Change 3. Tyrosine Phosphorylation

  21. Intracellular Signaling Pathways

  22. Signal Termination

  23. 3 Steps to activation • Ligand-induced oligomerization orconformational change • Autophosphorylation/crossphosphorylation • Recruitment of signaling molecules tophosphorylated tyrosines (“signalingcomplexes”) • Termination of Signaling (endocytosis)

  24. Intracellular vs. Transmembrane Receptor Tyrosine Kinases:Phylogenetic tree of tyrosine kinases

  25. Cytoplasmic Tyrosine Kinases

  26. Tyrosine kinase-derived oncogenes

  27. Dominant Negative Receptors:VEGFR-3 mutations in hereditary lymphedema ss S641P P1114L VEGF-R3

  28. Further reading Schlessinger, J. (2000): Cell Signaling by Receptor Tyrosine Kinases. Cell, Vol. 103, 211-225.

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