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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signal transduction B-CELL RECEPTOR SIGNALING TÁMOP-4.1.2-08/1/A-2009-0011 B-cell development • Haematopoietic development is a highly regulated multistep process in which pluripotent HSC differentiate through intermediate progenitors to mature cells in the blood • These processes are regulated by transcription factors and signaling pathways • The generationof lymphoid progenitors depends on: c-Kit, Flt3, and IL-7R TÁMOP-4.1.2-08/1/A-2009-0011 Early lymphopoiesis depends on: • PU.1: crucial for myeloid and lymphoid progenitors • IKAROS: controls development of lymphoid progenitors • Bcl11a: zinc finger transcrition factor, in its absence development is blocked in CLP • E2A: helix loop helix protein, B-cell fate determinant, turns on B-cell specific genes • EBF: early B-cell factor, B-cell fate determinant, turns on B-cell specific genes • Pax5: in its absence cells are blocked at pro-B stage, self renew, broad developmental potential. Pax5 represses non- The stage specific crucial events involved in B lymphoid commitment TÁMOP-4.1.2-08/1/A-2009-0011 LMPP Lymphoid priming CLP B-lineage priming BCP B-lineage commitment E2A/IKAROS/PU1 E2A/EBF1 EBF1/PAX5 RAG1/2, TdT, IgH, IL-7Rα, Notch-1, Ebf1 CD19, Tcf4, Aiolos, Irf4, Irf8, CD55 λ5, VpreB1, mb1, B29, OcaB, Pax5 LMPP: lymphoid primed multipotent progenitor, CLP: common lymphoid progenitor, BCP: B lineage committed progenitor Genetic control of lineage commitment in early lymphopoiesis TÁMOP-4.1.2-08/1/A-2009-0011 Low level of PU.1 → IL7Ra expression → lymphoid lineages (IL7Ra+) PreDC PreNK Id2 Id2 Ikaros HSC IL-7Ra+ CLP EA2 EBF PU.1 low PU.1 high Notch IL-7RaMyeloid prog. Pro-T Pax5 Pro-B TÁMOP-4.1.2-08/1/A-2009-0011 Early B-cell development in the bone marrow Ikaros c-Kit Fit3 PU.1 HSC Bcl11a Il-7R E2A EBF (DH ► JH) DH ► JH DH ► JH ELP CLP Prepro-B Myeloid Erythroid T Pax5 Foxp1 VH ► DHJH Pro-B Pre-BCR+ Large pre-B VL ► JL Small pre-B BCR+ Imm. B NK A schematic diagram of early B lymphopoiesis, showing the successive differentiation stages and the rearrangement status of IgH and IgL genes TÁMOP-4.1.2-08/1/A-2009-0011 The Ig gene rearrangement • DH–JH rearrangements are initiated in the earliest lymphocyte progenitors (ELPs) at a low level and are completed as the cell progresses to the CLP and prepro-B cell (also referred to as CLP2) stage. • VH–DJH recombination takes place in pro-B cells, and successful rearrangement leads to expression of the Igm protein as part of the pre-BCR in large pre-B cells. • Subsequent rearrangement of the IgL locus in small pre-B cells results in the expression of the BCR (consisting of m heavy and k or l light chains) on immature B cells (Imm. B). • The approximate points of the developmental arrest in mice that have defective transcription factors PU.1, Ikaros, Bcl11a, E2A, EBF, Pax5 and Foxp1 (black) or signalling components involved in signalling through Expression pattern of transcription factors involved in B cell commitment and differentiation TÁMOP-4.1.2-08/1/A-2009-0011 Progenitor CMLP, CLP PU.1 E2A EBF Ikaros Pax5 LEF-1 NF-kB Aiolos Bcl-6 Blimp-1 XBP-1 Commitment to B lineage Bone marrow PreB → Imm.B Peripheral maturation Germinal center Plasma cells TÁMOP-4.1.2-08/1/A-2009-0011 Immunreceptor Tyrosin-based Activation Motif Activating receptors Inhibiting receptors Immunreceptor Tyrosin-based Immunreceptor Tyrosin-based Ativation Motif (ITAM): Inhibition Motif (ITIM): D/E-x2- YxxL/I-x6-9Yx2L/I L/V/S-YxxL/V ITAM ITAM ACTIVATION ITAM ITIM INHIBITION TÁMOP-4.1.2-08/1/A-2009-0011 Acute antigen signaling Antigen BCR PlP2 Iga PlP3 Igβ PI3K P P P P P P P P SYK SYK LYN LYN BTK PLC2 BLNK VAV GRB2 SOS DAG PKC IP3 Ca2+ RAS ERK Transcription factors Proliferation, activation and antibody secretion TÁMOP-4.1.2-08/1/A-2009-0011 Co-stimularory pathways of BcR signaling BCR CD19 BAFFR Plasma membrane PIP2 LYN Igβ Iga PIP3 PI3K TRAF3 SYK ITAM TRAF3 AKT1 P TRAF2 DAG P PLC2 BLNK IP3 PKCβ GRB2 RAS Noncanonical NF-B1 pathway NIK BTK CARMA1 Ca2+ MALTI RAF BCL10 IKKa IKKβ p100 RELB p52 RELB MEK IKK Canonica l NF-B1 pathway NFAT p50 p65 ERK NF-B2 NF-B1 Cytoplasm REL Nucleus P100 Anti-apoptotic proteins Such as BCL-XL and MCL1 TÁMOP-4.1.2-08/1/A-2009-0011 Long term BcR stimulation BCR CXCR4 Pl(4,5)P Pl(3,4,5)P3 2 Iga Igβ PI3K P P P P P P Pl (3,4)P2 SYK SYK P BAFFR P LYN PLC2 BLNK VAV GRB2 ? SHIP1 LYN BTK Migration SOS DAG PKC IP3 Ca2+ RAS ERK DOK Survival Proliferation, activation and Transcription factors antibody secretion TÁMOP-4.1.2-08/1/A-2009-0011 The positive (CR2) and negative (FcgRIIb) B cell regulation model antigén C3d CD21(CR2 ) CD19 BCR CD81 PIP3 Lyn P P P P ab ab Syk P P Gab1 PIP3 Ras/MAPK Syk Lyn Lyn PI3- K P P PI3K P P P Vav P TÁMOP-4.1.2-08/1/A-2009-0011 Role for lipid rafts in Bcell activation CD45 CD22 BCR BCR Iga/β Lipid raft LYN ITIM ITAM LYN Antigen binding CD45 CD22 BCR BCR Iga/β LYN Receptor downregulation LYN Internalization P P P P P P P P SYK Antigen targeting SYK Signal transduction TÁMOP-4.1.2-08/1/A-2009-0011 Lipid rafts • The plasma membrane is composed primarily of sphingolipids, (glycerol)phospholipids and cholesterol. • Sphingolipids differ from most phospholipids in that they have long, largely saturated acyl chains that allow them to pack tightly in a bilayer, forming a gel phase in which there is very little lateral movement or diffusion. • The gel phase of the sphingolipids is altered by the association of cholesterol, which condenses the packing of the sphingolipids by occupying the spaces between the acyl chains. TÁMOP-4.1.2-08/1/A-2009-0011 Overview of BcR signaling BCR Antigen CRAC channel CD19 Ca2+ FcRIIB1 Lipid raft aggregation BCR Internalization Iga Gab Igb P13K p110 p85 BCAP SHIP2 Shc PIP3 GRB2 SHIP2 SHIP1 Cbl Bam32 clathrin CD22 Syk ezrin SHIP1 Pl(4,5)P2 PIR-B SHIP2 Nck BLNK PRK2 Lyn CD19 VAV IP3 Bam32 CD19 PIP3 Cytoskeletal rearrangments and integrin activation GRB2 LAB SOS Bam32 IP3R Intracellular Ca2+ store ER Glycolysis Akt ATP generation DAG TSC2 Ras GAP Ras Ca2+ PKC Ras GRP TAK1 DAG Riam Glucose uptake Ca2+ BLNK Rac RapL Dok-3 STIM1 Btk CD45 PLC2 Rac/ cdc42 Rho PTEN RhoA Lyn GSK-3 CARMA1 Rheb Bcl 10 CaM MALT1 Rap MEKKs Dok-1 c-RAF CD19 MKK3/4/6 IKK MKK4/7 Ca2+ PKC MEK1/2 Proteasomal degradation CD40 Cytoplasm Nucleus p38 JNK1/2 Erk1/2 p38 JNK Erk1/2 CREB mTOR FcgRIIB1 ATF-2 Jun Bcl-6 Egr-1 NF-B Transcription Bcl-xL Bfl-1 P70 S6K lB lB Elk-1 Calcineurin NF-B NFAT CaMK Oct-2 Ets-1 NFAT Protein synthesis Growth arrest, apoptosis Akt Transcription FoXO
