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Fcg receptor 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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Fcg receptor 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 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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