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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

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(1)

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

(2)

FCG RECEPTOR SIGNALING

Tímea Berki and Ferenc Boldizsár Signal transduction

at the University of Pécs and at the University of Debrecen

Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

(3)

FcRI

Types of human Fc receptors

Activating Fc Receptors Inhibitory Fc Receptor

FcRIIA FcRIIC FcRIIIA FcRIIIB FcRIIB

High Low-medium Low-medium Low-medium Low-medium Low-medium FcRIIA131H

FcRIIA131R FcRIIIA158V

FcRIIIA158F

FcRIIB232I FcRIIB232T

Human

Affinity Alleles

2

N N

C C

C

N N

C

N

C

2

N N

C C

C

N

C N

N

C GPI

ITIM ITAM

(4)

Mouse Fcgamma receptors

ITAM

2

N N

C C

C N

Low-medium

2

N N

C C

C N

Low-medium

N

C

Low-medium

FcRII FcRIV FcRIIB

FcRI

2

N N

C C

C N

High

ITIM

Mouse

Affinity

Activating Fc Receptors Inhibitory Fc Receptor

(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)

Activatory Fc receptor signaling

2

  

2

FcRIII Immune complex

Plasma membrane

Cytoplasm

Ca2+

LYN ITAMs SYK

P P

RAS SOS

PlP3

PLC

BTK PlP2

Ca2+

Downstream signalling pathways

(ERK, p38, JNK) Cell activation

ADCC Phagocytosis

Cytokine release Oxidative burst

PI3K

RHO PKC

RAC DAG IP3

Ca2+

ER

(7)

Steps of Fc signaling

1 Src kinase-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 Ca 2+ mobilization

(8)

Inhibitory Fcγ receptor signaling

SHIP FcRIIB

P

 BCR

Ig Igβ

ITIM LYN

PLC

BTK

No membrane recruitment

RAS SHC DOK

Simultaneous cross-linking

Inhibition of calcium flux and proliferation

PlP

3

PlP

2

(9)

Inhibitory Fcγ receptor signaling

ITIM BTK P cABL

JNK Apoptosis FcRIIB

Immune complex

(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

SYK SYK

SHIP SYK

P P

P P

P P

P P P

P

P P

2

  

2

FcRI FcRIIB FcRIIA FcRIIIA

Ca2+

Ca2+

ITAM

ITIM

RAS

PLC

BTK

RAC

DAG

IP3

Ca2+ ER

Actin polymerization

Phagocytosis

Cell proliferation

Actin polymerization and remodelling

Cytokine release ADCC

Degranulation

Proinflammatory responses Co-ligation to

Activation partner

Phagocytosis

VAV PYK2

PI3K PIP3

SYK

JNK BLNK

PKC

p38

Src Family PTKs

Src Family PTKs

Rho family GTPases

MAPK pathway

IgG Ag

Calcium signaling

CaCn

IP3R

(12)

Mediators produced by cells

Triggering agents and regulatory cytokines

IL-5 IL-3 GM-CSF

IL-5R IL-3R

IL-4 Eosinophil

SCF IgE

FcRI

Basophil

IL-5 and IL-13

IgG IL-4

KIT

Mast cell

IL-4R

Histamine

TLR

Bacteria and other TLR ligands

Monocyte/

macrophage

IL-1, IL-6 and TNF FcR

cytokines

(13)

phagocytosis

P SYK P

P P

2

FcRIIIA

P P

FcRIIA

P P

P P

2

FcRI

ITAM IgG

Ag IgG opsonized particle

Src Family PTKs

PLC2

DAG IP3 PI3K

Ca2+

PKC

Actin polymerization and particle internalization

Src Family PTKs

Src Family PTKs

Phosphorylation of ITAMs

(14)

phagocytosis I

2

FcR IgG

Pathogen

Effector cell

Ag

D2

(15)

phagocytosis II

Antibody

Microbe

Fc receptor

(16)

ADCC

Lytic enzymes Perforin TNF

Granzymes Neutrophil

NK cell

Eosinophil

Macrophage Ab bound to Ag

and Fc receptor

Fc receptor

Target cell

Surface Ag

Hivatkozások

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