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Tyrosine kinase -linked receptors part 1 Cytokine- chemokine signaling

Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s P rogrammes at the University of Pécs and at the University of Debrecen Identification number : TÁMOP-4.1.2-08/1/A-2009-0011.

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Tyrosine kinase -linked receptors part 1 Cytokine- chemokine signaling

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signaltransduction Tyrosine kinase-linked receptors part1Cytokine-chemokine signaling

  3. Cytokine groups • Structural: • 14 a-helix bundle family • IL-2 subfamily • IFN subfamily • IL-10 subfamily • 2IL-1 family • 3IL-17 family • Functional: • 1Haematopoietic(EPO, TPO, G-CSF, GM-CSF, SCF etc.) • 2Lymphocytedifferentiation/activation • Th1: IL-2, TNF, IFNg • Th2: IL-4, IL-5, Il-13; IL-17, IL-23 • 3Inflammatory(IL-1, IL-6, TNFa)

  4. Cytokinereceptors Receptors for erythropoietin, growth hormone, and IL-13  β Receptor for IL-3, IL-5, and GM-CSF share a commonchain,CD131 orβc(commonbetachain) Class I cytokine receptor (hematopoietinreceptorfamily) Receptor for IL-2, IL-4, IL-7, IL-9 and IL-15 share a commonchain CD132 orc(common gamma chain). Il-2 receptor also has a thirdchain, ahighaffinitysubunitIL-2R(CD25) Interferon-, -β, and -receptor, IL-10 receptor Class II cytokine receptor Tumor necrosisfactor (TNF) receptors I and II, CD40, Fas (Apo1, CD95), CD30, CD27, nervegrowthfactor receptor TNF-receptor family CCR1-10, CXCR1-5, XCR1, CX3CR1 Chemokine-receptorfamily

  5. Characteristics of multichaincytokinereceptors CNTF LIF/OSM GM-CSF receptor subfamily (commonβsubunit) Il-6 receptor subfamily (common gp130 subunit) Il-2 receptor subfamily (commonsubunit) IL-6 IL-11 GM-CSF IL-3 IL-5 IL-2 IL-15 IL-7 IL-9 IL-4 IL-2R IL-15R GM-CSFR IL-3R IL-5R CNTFR      IL-2Rβ IL-9R IL-7R IL-2Rβ β β β gp130 gp130 gp130 IL-4R gp130

  6. Overview of cytokinesignalling Phosphorylated STATs form dimers that translocate into the nucleus to initiate new gene transcription Cytokinereceptorsconsist of atleasttwochains, thecytoplasmaticdomainsofwhichbind Janus kinases (JAKs) Cytokine binding dimerizes the receptor, bringing together the cytoplasmic JAKs, which activate each other and phosphorylate the receptor Transcription factors (STATs) bind to the phosphorylated receptors, and are in turn phosphorylated by the activated JAKs JAK JAK JAK JAK JAK JAK JAK JAK JAK JAK P P P P P P P P P P P P P P P P STAT STAT

  7. The structure of JAK and STAT proteins JAK structure JH7 JH6 JH5 JH4 JH3 JH2 JH1 FERM "SH2" yKI KI 0 200 400 600 800 1000 1200 P STAT structure Y NH2 Coiled coil DBD Lk SH2 TAD 0 200 400 600 800

  8. JAK I JAK1 JAK2 JAK3 Tyk2 Y1038/Y1039 Y1007/Y1008 Y980/Y981 Y1054/Y1055 Proline rich membrane proximal part of Cytokine Receptors • Activation Y residues: FERM domain: band 4.1, ezrin, radixin and moesin Pseudokinase Kinase JH7 JH6 JH5 JH4 JH3 JH2 JH1 FERM "SH2" yKI KI 0 200 400 600 800 1000 1200 JH=Janus homology domain

  9. JAKII

  10. STAT I Receptor recruitment and dimerization Bindingof regulators Dimerization DNA-binding Nuclear transport Transcriptional activation DNA-binding Linker P Y NH2 Coiled coil DBD Lk SH2 TAD 0 200 400 600 800

  11. Human STATs

  12. STAT II

  13. Regulation of JAK/STAT signaling • Phosphatases • SHP-1/2, CD45 – JAK • SHP-2, PTP1B, TC-PTP, PTP-BL – STAT • Nuclear export/import • NES (nuclear export sequence) • NLS (nuclear localization sequence) • SOCS (suppressors of cytokine signaling) eg. PIAS (Protein Inhibitor of Activated STATs) • Ser-phosphorylation, acetylation, o-glycosylation of TAD

  14. JAK inhibitors • Treatment: • Polycythemiavera, thrombocytemia, • Myeloidmetaplasia, myelofibrosis • Psoriasis • RA • Examples: • Lestaurtinib • Tofacitinib • Ruxolitinib

  15. Chemokines • 90-130 aa. polypeptides • Functions: • Chemotaxis for different leukocytes: • Regulation of normal leukocyte traffic • Recruitment of cells to inflammatory sites • Enhancement of cell adhesion • Activation of effector leukocytes • Development of the inflammatory reaction • Development of normal lymphoid tissues

  16. ChemokinesignalthroughreceptorscoupledwithG-proteins Chemokine receptor Ca2+ channels  β  G protein GTP Adenylyl cyclase ? ? PLCβ2   DAG IP3 β ? GDP PKC Ca2+ Ras cAMP Adhesion Cytoskeletal rearrangment Actin polymerization Differentiation, proliferation Chemotaxis

  17. Chemokinesignalingpathways Chemokines Ca2+ channel Ca2+ Chemokine receptor  Plasma membrane β  PLCβ PIP2 JAK2 Cytoplasm GTP STAT5 PYK2 Ca2+ PKC Ca2+ Crk IP3 CAS PLC   β PI3K GDP GRK PTK Rho GRB2 DAG PDK MAPK pathway β-Arrestin RAS Akt/ PKB PLA2 Internalization Degradation Recycling Akt/PKB pathway Rho pathway Ras pathway p38 JNK PKCβ Cellactivation Nucleus NF-B c-Jun Elk-1 Elk-1 SRF Elk-1 NF-B c-Fos Geneexpression and apoptosis

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