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Tyrosine kinase -linked receptors PART 2 Growth factors

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 2 Growth factors

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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 PART2Growth factors

  3. Growth factors (GFs) • Small molecular weight soluble mediators • They control: • 1 Proliferation • 2 Survival • 3 Metabolism • 4 Tissue differentiation • Important implication in tumors • Cytokines – growth factors

  4. Growth factors (GFs) – History • How to propagate cells under in vitro conditions (turning of the 19th-20thcentury)? • Rous:experiments with chicken tumor (sarcoma) cells (RSV) • Carrel: In simple buffered salt solution the cells did not proliferate – trials with diluted plasma/serum • Temin and Dulbecco:precise requirements for tissue culturing: • Reduced serum need of tumor cells – enhanced capacity of tumor cells to respond to proliferation signals • Serum supported cell growth rather than plasma – PDGF • Rita Levi-Montalcini, Stanley Cohen– NGF and EGF • Transplantation of an actively growing mouse tumor into chicken inducedthe great amplification of nerve fibres into the tumor mass

  5. Growthfactors

  6. Receptorswith TK activity • Receptor TyrosineKinases (RTK) • e.g. PDGF, insulin, EGF, VEGF and FGF receptors • Tyrosine-KinaseAssociatedReceptors • Receptorsthatassociatewithproteinsthathavetyrosinekinaseactivity (CytokineReceptors) • Receptor TyrosinePhosphatases • e.g. CD45 protein of T cells and macrophages

  7. “Complete” and “incomplete” receptor tyrosine kinase “Complete” receptor tyrosine kinase “Incomplete” receptor • Adaptor • Cytoplasmic • non-receptor • tyrosine kinase • Signal • Signal

  8. Receptortyrosinekinase(RTK)families • 90 unique Tyr kinases in the human genome, 58 are RTKs • Growth factor, cytokine and hormone receptors • Classes:

  9. Kinase-phosphatasebalance Phosphorylase kinase (ser/thr kinase) ATP ADP Phosphorylase b Phosphorylase a P Phosphorylase b Phosphorylase a P P Inactive Active PP1c (ser/thr phosphatase) Inactivep56Lck Primedp56Lck Active p56Lck CD45 (tyr phosphatase) Y505 Y505 P P Y394 P Y394 Y394 ADP ATP Csk (tyrkinase)

  10. Growthfactorreceptors Ltk Alk FGFR1 FGFR2 FGFR3 FGFR4 PDGFR PDGFRβ CSF1R Kit Kit2 VEGFR1 VEGFR2 VEGFR3 Met Ron Sea TrkA TrkB TrkC Tie Tie2 Ret EGFR ErbB2 ErbB3 ErbB4 INSR IGF1R IRR Eph Eck Eek Erk Elk Ehk1 Ehk2 Sek Hek Hek11 Cek-9 Myk-1 Myk-2 Ryk Ros Ror1 Ror2 Torpedo Torso Axl Mer Sky DDR EGF-like Factor VIII-like C1r-like Cysteine-rich Fibronectin III Kinase Kringle Glicyne-rich Cadherin IG-like Leucine-rich Acid-box

  11. Receptor-likePTPs (21) R1/R6 R2B R2A R4 R5 R3 R7 R8 PTP domain Kinase-interactingdomain RGDS motif PTP pseudo-phosphatase domain Src homology 2 Fibronectin III SEC14 domain CD45 (RC) PTP (RM) PTP (RK) PTP (RT) PTP (RU) LAR (RF) PYP (RS) PTP (RD) PTP (RA) PYP (RE) PTP (RG) PYP (RZ1) PTPβ (RB) DEP1 (RJ) SAP1 (RH) GLEPP1 (RO) PTPS31 (RP) PCPTP1 (RR) STEP (N5) IA2 (RN) IA2β (RN2) MAM domain Proline-rich FERM domain IG-like Cadherine-like PDZ domain BRO-1 homology Glycosylated Carbonicanhydrase-like Histidine domain

  12. NontransmembranePTPs (17) NT1 NT2 NT3 NT4 NT5 PTP1B (N1) TCPTPβ (N2) SHP1 (N6) SHP2 (N11) MEG2 (N9) BDP1 (N18) PTP-PEST (N12) LYP (N220) PTPH1 (N3) MEG1 (N14) PTP domain Kinase-interactingdomain NT6 NT7 NT8 NT9 RGDS motif PTP pseudo-phosphatase domain Src homology 2 Fibronectin III SEC14 domain MAM domain Proline-rich FERM domain IG-like Cadherine-like PDZ domain BRO-1 homology Glycosylated PTPD1 (N21) PTPD2β (142) HDPTP (N23) PTPTyP (N20) HePTP (N7) Carbonicanhydrase-like Histidine domain PTPBAS (N13)

  13. Growthfactorreceptors and tyrosinephosphorylation P P PDGFR EGFR P P P P Phosphotyrosine Y559 Y581 Y716 Y741 Y751 Y771 Y1009 Y1021 Phosphotyrosine Y992 Y1045 Y1068 Y1086 Y1148 Y1173 P P P P P P P P P P P P P P P P P P Shc PI3K Cbl SLP76 GRB2 Crk SHP-1 SRC IRS-1 Abl Nck STAT1 PLCg p120 Ras-Gap

  14. Receptor tyrosinekinase(RTK) signaling Ligand RTK Dimerization P P P P P P P P GRB2 SOS PI3K PDK1 JAK PLC Ras Akt PKC Src Raf STAT Erk Proliferation Survival Migration Cell cycle progression Transcription

  15. GF receptor signalingpathwaysI Ligand RTK Plasmamembrane P P PIP3 PIP2 PIP3 Targets P P PDK1 Akt P P P P PI3K P GRB2 P P Targets Targets P P Shp2 P GRB2 P GRB2 P P GRB2 Shp2 GRB2 SOS Ras Erk Targets Targets

  16. GF receptor signalingpathwaysII Ligand RTK Plasma membrane P P PIP2 Cytoplasm P P P P P P PH PLC SH2 SH2 SH3 PLC C2 IP3 Ca2+ Cbl PKC DAG P

  17. Overview of EGF signaling EGF Vav2 EGFR PTP + E2Ub - - STAT1 STAT3 PLC H2O2 GRB2 Cbl IP3 NADPH synthesis DAG Gab1 SOS Targetgenes Shc Ca2+ + - - Cdc42 /Rac PKC Rac PI3K Ras Src DOK Targets PIP3 - Raf MEKK MEKK4 Akt PDK1 ADAM Ras GAP MAPKK MKK2 MKK4 Nck + GRB2 - Targets HB-EGF FAK Bad FKHR MAPK MAPK p38 JNK Gab1 Src PAK1 Paxillin C-Fos MAPK Shp2 RSK2 p53 Jun CAS WASP Rac JNK AP1 Apoptosis CREB Cell cycle Cytoskeleton

  18. General characteristics of GF signaling Input layer Diverse input signals (MultipleRTKs) + - Conservedcore processes - System control + + Diverseouputevents (transcriptionalresponses, cytokeletalchanges, etc) Output layer

  19. Different GF receptorsusethesamesignalingpathways EGF TGF β-cellulin Amphiregulin HB-EGF PDGF-C β-cellulin NRG2 NRG3 No specific ligands PDGF-B PDGF-D Heregulins VEGF-B VEGF-A VEGF-C VEGF-D PDGF-A SCF P P P P P P P P EGFR Her2 Her3 Her4 VEGFR1 VEGFR2 VEGFR3 PDGFR-a PDGFR-b c-kit P P P P P P P P P P P P P P P P P P GRB2 SOS Ras Rac CDC42 Rho P P P P P P P P P P P P P P P P P P ERK pathway JNK pathway p38 pathway Raf MEKK Tak PI3K Sorafenib Sirolimus P P P P P P P P P P P P P P P P P P Panitumumab Temsirolimus Erlotinib Midostaurin MEK1/2 MKK4/7 MKK3/6 P P P P P P P P P P P P P P P P P P Akt Gefitinib Motesanib Lapatinib Pazopanib Erk JNK p38 mTor Leflunomide Enzastaurin Trastuzumab Sunitinib Imatinib Vandetanib Everolimus Bevacizumab Cellsurvival Proliferation Apoptosisresistance Cetuximab Metastasis Angiogenesis

  20. Natriureticpeptidesignaling ANP BNP CNP P P Natriureticpeptide Natriuretic peptide P P P P Kinase Receptor NPR-C NPR-A (GC-A) NPR-B (GC-B) ATP P P P P P P P P P P P P Basal P P P P Ligand binding domain P P P P P P Plasma membrane Kinase homology domain Desensitised Hormone bound Hinge region ATP ATP P GTP GTP GTP cGMP cGMP cGMP Phosphatase Guanylyl cyclase domain Physiologic response ↑NP degradation ↓cAMP? ↑ IP3? ↑ Vasorelaxation ↑ Diuresis, natriuresis ↓ Renin, aldosterone ↓ Cell proliferation ↓ Cardiac fibrosis ↑ Vasorelaxation ↓ Cellproliferation ↑ Long bonegowth Active

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