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