Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

FCG RECEPTOR SIGNALING

Tímea Berki and Ferenc BoldizsárSignal transduction

Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

TÁMOP-4.1.2-08/1/A-2009-0011

FcRI

Types of human Fc receptorsActivating Fc Receptors Inhibitory Fc Receptor

FcRIIA FcRIIC FcRIIIA FcRIIIB FcRIIB

High Low-medium Low-medium Low-medium Low-medium Low-mediumFcRIIA131H FcRIIA131R

FcRIIIA158V FcRIIIA158F

FcRIIB232I

FcRIIB232T

Human

AffinityAlleles

2N N

C C

C

N N

C

N

C

2N N

C C

C

N

C

NN

C

GPI

ITIMITAM

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Mouse Fcgamma receptors

ITAM

2N N

C C

C

N

Low-medium

2N N

C C

C

N

Low-medium

N

C

Low-medium

FcRII FcRIV FcRIIB FcRI

2N N

C C

C

N

High

ITIM

Mouse

Affinity

Activating Fc Receptors Inhibitory Fc Receptor

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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 FcRIIA and C, and in the chains of FcRI and FcRIIIA.

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Activatory Fc receptor signaling

2 2

FcRIII

Immune complex

Plasma membrane

Cytoplasm

Ca2+

LYN

SYKITAMsP

P

RASSOS

PlP3

PLCBTKPlP2

Ca2+

Downstream signalling pathways (ERK, p38, JNK) Cell activation

ADCC PhagocytosisCytokine release Oxidative burst

PI3K

RHO PKC

RAC DAG IP3

Ca2+

ER

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Steps of Fc signaling1 Src kinase-mediated tyrosine phosphorylation of the

ITAMs 2 Following by SH2 domain-mediated recruitment of

Syk family kinases to ITAMs3 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

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Inhibitory Fcγ receptor signaling

SHIP

FcRIIB

P

BCR

Ig Igβ

ITIMLYN

PLCBTK

No membrane recruitment

RAS

SHCDOK

Simultaneous cross-linking

Inhibition of calcium flux and proliferation

PlP3PlP2

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Inhibitory Fcγ receptor signaling

ITIM PBTK cABL

JNK Apoptosis

FcRIIB

Immune complex

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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

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Overview of Fcγ receptor signaling

SYKSYKSHIP

SYKP

P

P

P

P

P

P

P

P

P

P

P

2

2

FcRI FcRIIA FcRIIIA FcRIIB

Ca2+

Ca2+

ITAMITIM

RAS

PLC

BTK

RAC

DAG

IP3 ERCa2+

Actin polymerization

Phagocytosis

Cell proliferation

Actin polymerizationand remodelling

Cytokine releaseADCCDegranulation

Proinflammatoryresponses

Co-ligation toActivation partner

Phagocytosis

VAV PYK2

PI3K

PIP3

SYK

JNK

BLNK

PKC

p38

Src FamilyPTKs

Src FamilyPTKs

Rho familyGTPases

MAPK pathway

IgG Ag

Calcium signaling

CaCn

IP3R

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Mediators produced by cells

Triggering agents and regulatory cytokines

IL-5 IL-3 GM-CSF

IL-5R IL-3R

IL-4

Eosinophil

SCF IgE

FcRI

Basophil

IL-5 and IL-13

IgG IL-4

KIT

Mast cell

IL-4R

Histamine

TLR

Bacteria andother TLR ligands

Monocyte/macrophage

IL-1, IL-6 and TNF

FcR

Triggering agents and regulatory cytokines

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Role of FcRs: enhanced phagocytosis

SYKP

P

P

P

2

FcRIIIA

P

P

FcRIIA

P

P

P

P

2

FcRI

ITAM

IgG

Ag IgG opsonized particle

Src FamilyPTKs

PLC2

DAG IP3 PI3K

Ca2+PKC

Actin polymerization and particle internalization

Src FamilyPTKs

Src FamilyPTKs

Phosphorylation of ITAMs

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Role of FcRs: enhanced phagocytosis I

2

FcR

IgG

Pathogen

Effector cell

Ag

D1D2D2

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Role of FcRs: enhanced phagocytosis II

AntibodyMicrobe

Fc receptor

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ADCC

Lytic enzymesPerforinTNF

Granzymes

Neutrophil

NK cell

Eosinophil

Macrophage

Ab bound to Agand Fc receptor

Fc receptor

Target cell

Surface Ag