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Understanding Fcγ Receptor Signaling Pathways in Medical Biotechnology Master’s Programs

This study explores novel social challenges of the EU in teaching materials of Medical Biotechnology programs. It focuses on Fcγ receptor signaling pathways, alleles, and roles in cell activation and inhibition.

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Understanding Fcγ Receptor Signaling Pathways in Medical Biotechnology Master’s Programs

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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 Fcg receptor signaling

  3. Types of human Fcreceptors Activating Fc Receptors InhibitoryFc Receptor FcRI FcRIIA FcRIIC FcRIIIA FcRIIIB FcRIIB Human N  N N N N N      2 2 N N N N GPI C ITIM C C ITAM C C C C C C C Affinity High Low-medium Low-medium Low-medium Low-medium Low-medium Alleles FcRIIA131H FcRIIIA158V FcRIIB232I FcRIIA131R FcRIIIA158F FcRIIB232T

  4. Mouse Fcgammareceptors ActivatingFcReceptors InhibitoryFc Receptor FcRI FcRII FcRIV FcRIIB Mouse N N N N     2 2 2 N N N N N N ITIM C C C ITAM C C C C C C C Affinity High Low-medium Low-medium Low-medium

  5. Role of ITAMs • ITAM is a specific sequence of amino acids (YXXL) occurring twice in close succession in the intracellular tail of a receptor. • After ligand binding, the tyrosine (Y) residue of the ITAM is phosphorylated by tyrosine kinases, and a signaling cascade is generated within the cell. • An ITAM is present in the intracellular tail of FcRIIA and C, and in the  chains of FcRI and FcRIIIA.

  6. ActivatoryFcg receptor signaling Immunecomplex FcgRIII Ca2+ 2 2   Plasmamembrane PlP2 PlP3 Cytoplasm LYN BTK PLC P SYK PI3K ITAMs RAC DAG IP3 Ca2+ P SOS RAS RHO PKC Ca2+ Cellactivation Downstreamsignallingpathways (ERK, p38, JNK) ER Cytokinerelease ADCC Phagocytosis Oxidativeburst

  7. Steps of Fcgsignaling • 1 Srckinase-mediated tyrosine phosphorylation of the ITAMs • 2 Following by SH2 domain-mediated recruitment of Syk family kinases to ITAMs • 3 Activation of PI-3 kinase • 4 Recruitment of adapter molecules like SLP-76 and BLNK • 5 Recruitment of enzymes like phospholipase C and Tec family kinases • 6 Generation of IP3 and DAG • 7 Intracellular free Ca2+ mobilization

  8. InhibitoryFcγ receptor signaling Simultaneouscross-linking BCR FcRIIB  PlP2 PlP3 LYN ITIM SHIP No membrane recruitment P DOK SHC BTK PLC Ig Igβ RAS Inhibition of calciumflux and proliferation

  9. InhibitoryFcγ receptor signaling Immunecomplex FcRIIB a a BTK ITIM cABL P Apoptosis JNK

  10. ITIM • The presence of only one YXXL motif is not sufficient to activate cells, and represents a motif (I/VXXYXXL) known as an Immunoreceptor tyrosine-based inhibitory motif (ITIM) • FcγRIIB1 and FcγRIIB2 have an ITIM sequence and are inhibitory Fc receptors: they do not induce phagocytosis but counteract the antigen-induced BcR signal on B cells and shut off B cell activation • The inhibitory signal is controlled by SHP-1 and SHIP-phosphatases

  11. Overview of Fcγ receptor signaling IgG Ag FcRI FcRIIB FcRIIA FcRIIIA Ca2+ g2 g2 a a a a CaCn PIP3 P P SYK SHIP ITIM SrcFamily PTKs P P P P P P SYK SYK ITAM Co-ligationto Activation partner P P P P Ca2+ PI3K Rhofamily GTPases SrcFamily PTKs IP3R SYK PLC IP3 Ca2+ ER VAV PYK2 BTK Calciumsignaling Actin polymerization and remodelling BLNK RAS DAG Phagocytosis Actinpolymerization RAC PKC MAPK pathway Degranulation ADCC Cytokine release Phagocytosis JNK p38 Proinflammatory responses Cell proliferation

  12. Triggeringagents and regulatorycytokines Triggeringagents and regulatorycytokines IL-5 IL-3 GM-CSF SCF IgE IgG IL-4 Bacteria and other TLR ligands TLR FcRI IL-5R IL-3R KIT IL-4R FcR Eosinophil Basophil Mast cell Monocyte/ macrophage IL-4 IL-5 and IL-13 Histamine IL-1, IL-6 and TNF Mediators produced by cells

  13. Role of FcRs: enhancedphagocytosis IgGopsonizedparticle Ag IgG FcRIIA FcRIIIA FcRI g2 g2 a a a P SrcFamily PTKs SrcFamily PTKs SrcFamily PTKs P P P P P SYK ITAM P P P P Phosphorylation of ITAMs PLC2 IP3 DAG PI3K PKC Ca2+ Actinpolymerization and particleinternalization

  14. Role of FcRs: enhancedphagocytosisI Ag Pathogen IgG D1 D2 D2 FcgR a g2 Effectorcell

  15. Role of FcRs: enhancedphagocytosisII Fc receptor Antibody Microbe

  16. ADCC Lyticenzymes Perforin Neutrophil TNF Granzymes Ab boundtoAg and Fc receptor NK cell Targetcell Eosinophil SurfaceAg Fc receptor Macrophage

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