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Manifestation of Novel Social Challenges in EU Medical Biotechnology Teaching

This research explores the manifestation of novel social challenges in the teaching material of Medical Biotechnology Master's programs at the University of Pécs and the University of Debrecen.

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Manifestation of Novel Social Challenges in EU Medical Biotechnology Teaching

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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 Receptor interactionssignalingcross-talk

  3. Introduction • Although there is a need for the precise separation of certain pathways to maintain the specificity of signals, upon complex physiological stimuli more pathways might be active inparallel. This creates a basis for interaction between active pathways. • Signaling pathways form a “network”. • Some proteins can participate in multiple pathways.

  4. Mechanisms of interaction • Synergism/antagonism • Direct protein interactions – large signaling complexes, organized by scaffold proteins and the cytoskeleton • Phosphorylation/dephosphorylation • Importance: when targeting a pathway never forget about potential interactions with other pathways!

  5. Levels of signal “cross-talk” • Cell surface receptors • Plasma membrane proximal signaling complexes • Cytoplasmic signaling complexes • Pathway merging / branching • Transcription factors

  6. More receptorsusingthesamesecondmessengersystem ACTH LH FSH Secretin Adrenaline Glucagon Adenylylcyclase ATP cAMP

  7. Growthfactor receptor –integrinsignalinginteraction ECM Growth factors Integrins PI3K PTEN IRS1 - ILK Nck2 Pinch IBPs - + GSK3 + -catenin LEF1 + PKB - + Cadherins Cyclins AP1 Suppression of apoptosis Angiogenesis Invasion, proliferation

  8. 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

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

  10. Ras – an important signaling switch EGFR P P P P K-RAS mutation controls 75% of EGFR-pathway B-RAF mutation: 1/4 EGFR-pathway PTEN mutation: 1/4 EGFR pathway PI3K mutation: 1/4 EGFR pathway P P GRB2 PI3K3R1 P P PI3K3CA SOS PTEN Akt Ras PLCe PLC JAK mTOR BRaf PKC STAT1/3 RAS-independent Erk

  11. BcR and FcβRIIB cross-talk Simultaneouscross-linking BCR FcRIIB a PIP2 PIP3 LYN ITIM SHIP No membranerecruitment P DOK SHC BTK PLC Ig Ig RAS Inhibition of calciumflux and proliferation

  12. Non-genomic GR signaling – interaction of GR with cytoplasmicTcR signaling proteins a a b b • Heat shock proteins (chaperons) organize multiprotein complexes • GR associates with Hsp-90 and ZAP-70 z z z z d d e e e e g g TCR TCR Plasmamembrane Lck Cytoplasm Lck HSP90 ZAP70 ZAP70 P HSP90 ?

  13. TNFR – GR cross-talk I TNF GC Plasmamembrane TNFR Cytoplasm Chaperone complex GR MAPK inactivation MAPK TF Nucleus Induction of anti-inflammatorygenes Tethering of pro-inflammatory TF TF GILZ, MKP-1, TTP, IBa TFRE GRE Inhibition of RNA Pol-IIphosphorilation Cofactorcompetition pTEFb P RNA Pol-II TF RNA Pol-II TF TF TF TFRE TFRE TFRE TFRE Chromatinmodulation: MSK1 removal Chromatinmodulation: HDAC recruitment MSK1 MSK1 TF HDAC2 TF TF P AC AC TFRE P TF TFRE AC TFRE H3 TFRE H3

  14. TNFR – GR cross-talk II TNF TNF GC Plasmamembrane TNFR TNFR Cytoplasm GR ROS Transcriptionfactorslike: NFkB, AP-1, IRFs,... MAPK TF GRE Nucleus Cofactorcompetition TF GR ROS HDAC2 TF TFRE

  15. Transcription factor cross-talk + : Induction of transcription – : Inhibition of transcription

  16. Convergence of signaling pathways Platelets Circulating cells and mediators EGF TNF ANG II PDGF 5HT (serotonin) ALK/End or BMPR 1-2 Cell surface receptors BMPs or TGF Anorexigens 5HT transporter G protein O-2 P Angiopoiethin NO NO restores hypoxia blocks SMADs Intracellular signalling TIE MAP Kinases K+ channels Endothelin B Virus infection? HIV, HHV-8 Apoptosis SMC tone ERK JNH A ES Receptor VEGF Estrogen Growth Cytokines ↓Apoptosis Nuclear Transription Factors KDR AML Gene activation or repression Proliferative phenotype Apoptosis Other products Elastase Tenascin-c

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