1 / 18

Enzyme-linked receptors

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.

thao
Download Presentation

Enzyme-linked receptors

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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 Enzyme-linkedreceptors

  3. Receptorswithenzymeactivity • Receptor TyrosineKinases (RTK) • e.g. PDGF, insulin, EGF, VEGF and FGF receptors • Receptor TyrosinePhosphatases • e.g. CD45 (cluster determinant-45) protein of T cells and macrophages • Receptor GuanylateCyclases • e.g. natriureticpeptidereceptors • Receptor Serine/ThreonineKinases • e.g. activin and TGF-βreceptors • Tyrosine-KinaseAssociatedReceptors: receptorsthatassociatewithproteinsthathavetyrosinekinaseactivity (CytokineReceptors)

  4. Receptor classesI

  5. Receptor classesII

  6. Introduction “Complete” receptor tyrosine kinase “Incomplete” receptor • Adaptor • Cytoplasmic • non-receptor • tyrosine kinase • Signal • Signal

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

  8. Receptor tyrosinekinasefamily 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

  9. Main steps of RTK activation • 1Ligand binding • 2Dimerization • 3Autophosphorylation • 4Signal complex (adapter proteins, kinases etc.)

  10. Dimerization of GF receptors Dimerization Plasmamembrane Cytoplasm ATP ATP P P P P P P P P P P Juxtamembraneregion Activation and catalyticloop (substrateprecluding) C-terminalregion Activation and catalytic loop (substrate accessible)

  11. Autophosphorylation of RTKs 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

  12. Members of the initial signal complex • Enzymes/transcription factors: • Src/Syk family kinases, SHP-1, PLCg, Sos, Vav, RasGAP, STAT1 etc. • Adaptors/regulators: • Grb2, SLP-76, SOCS1, Nck, Shc, Crk-L, p85 etc. • Adaptors/docking proteins: • FRS2, IRS1, DOK1 etc.

  13. Members of thesignalingcomplex Growthfactor/Hormone Receptor PTK Plasma membrane Cytoplasm PI3K SHC GRB2 SOS RAS MEK Y Y Y Y SRC PKC RAF MAPKs Y Y RSK PLCg FAK Transcriptionalregulation Differentiation Differentiation/Growth Nucleus

  14. Ras-MAPK pathway Growthfactor/Hormone Receptor PTK Plasmamembrane RAS Active RAS Cytoplasm RAF ? SOS GDP P P P P P P P P GTP GRB2 Guanine nucleotide exchange factor (GEF) MEK1 MEK1 P P P P P P P P Adaptor ERK2 ERK2 ERK2 ERK2 + Elk-1 Elk-1 Nucleus Genetranscription SRE Elk-1 cFos SRF AP-1

  15. Parallel MAPK pathways ERK pathway p38 pathway JNK pathway Ligands and activators Mitogens Stress/Cytokines MEKK1, DLK, MLK2, ASK, TAK1, TAO, TAO2 MAPKKK A-raf, B-raf, C-raf MAPKK MEK1, MEK2 MEK3, MEK6 MEK4, MEK7 PDK1 MAPK ERK1, ERK2, ERK5 ERK3, ERK4 p38a, b, d JNK1, 2, 3 RSK1 RSK2 RSK3 RSK4 MSK1 MSK2 MNK1 MK2 MK3 MK5B MK MNK2

  16. MAPK-activated kinases(MKs) • RSK (ribosomal S6 kinases) • cytoplasmic (initiation factors of translation, apoptosismachinery, oestrogenrec., Sos), phosphorylated form can translocate to nucleus (ATF4, c-Fos, SRF) • MSK (mitogen- and stress-activated kinases) • in nucleus (CREB, histone H3, HMGN1, ATF1) • MNK (MAPK-interacting kinases) • translation initiation complex

  17. Turning-off the pathway • Phosphatases PTP1B, SHP1/2, DEP1 • Phosphorylation of GEF (Sos) decreases the affinity to the adapter (Grb2) • Removal of cell surface receptors by endocytosis

  18. RTKs Integrins Ca2+ MAPK/ERK ingrowth and differentation Ion channels Ca2+ Ras SOS SOS Pax RTKs Tal GRB2 Shc FRS2 IRS Rap1 GRB2 CAS PLCg FAK C3G CRK Fyn PI3K Spry Cytoplasm Src Ca2+ PYK2 PAK elF4B Rac cAMP Spred rpS6 B-Raf PKA c-Raf PKC 14-3-3 IkBa B-Raf c-Raf Tpl2/ Cot1 IMP MEK1 P14 Heterodimer Filamin A PD98059 U0126 MP1 cPLA2 p90RSK C-TAK1 PP1/ PP2At MEK1/2 Erk1 KSR Transiation control SOS TSC2 MNK1/2 Late endosome Ion channels, receptors eEF2 Kinase DAPK GSK-3 Cytoskeletal proteins Erk1/2 MPK-3 Bim Cell adhesion PEA-15 METTL1 BAD nNos PPARg cdc25 Progression of cell cycle P27 KIP1 p90RSK MSK1/2 MPK-1/2 BUB1 Erk1/2 Nucleus C/EBPβ MITF Nur77 ERa C-Fos SRF ETV1 ATF1 CREB FoxO3 TIF1A Elk-1 Ets ER Ran BP3 ATF4 Mad1 ETV1 Myt1 TIF1A HMGN1 Histone H3 Pax6 C-Myc/ N-Myc C-Fos UBF Stat1/1

More Related