B and T lymphocyte antigen receptor structure

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B and T lymphocyte antigen receptor structure
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Immunoreceptor Tyrosine-based activation motifs
(ITAMs) are present in multiple copies in the
cytoplasmic domains of antigen receptors
a b
hz1 Q L Y N E L N L G R R E E - Y D V L hz2 G L Y
N E L Q K D K M A E A Y S E I hz3 G L Y Q G L S T
A T K D T - Y D A L hCD3g Q L Y Q P L K D R E D
D Q - Y S H L hCD3e P D Y E P I R K G Q R D L - Y
S G L hCD3d Q V Y Q P L R D R D D A Q - Y S H
L mIga N L Y E G L N L D D C S M - Y E D
I mIgb H T Y E G L N I D Q T A T - Y E D I
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ITAM motifs were shown to be sufficient for
signaling when expressed as chimeras, independent
of the receptor
CD8
a b
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Receptor aggregation can initiate signaling
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Initiation of Antigen Receptor signaling depends
upon non-receptor protein tyrosine kinases (PTKs)
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Three types of tyrosine kinases are involved in
antigen receptor signaling. Each has a
conserved catalytic domain and protein
interaction domains
Src kinase family (e.g. Lck, Fyn, Lyn, Blk)
Syk/ZAP-70 family
Tec kinase family (e.g. Itk,Btk,Rlk)
Catalytic domain
SH2
SH3
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Src family kinases are responsible for the
tyrosine phosphorylation of ITAM motifs in
antigen receptors
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Receptor phosphorylation leads to recruitment and
activation of the ZAP-70 tyrosine kinase
a b
a b
Lck
ZAP-70
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Tyrosine kinase activity is regulated by tyrosine
phosphorylation and protein interaction domains
Lck
The Csk kinase phosphorylates the inhibitory
tyrosine and the CD45 phosphatase can
dephosphorylate this tyrosine. Src kinases
autophosphorylate the activating tyrosine.
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• Models of antigen receptor signal initiation
• Receptor-associated kinase aggregation leads to
  kinase activation and ITAM phosphorylation.
• 2. Receptor aggregation leads to co-localization
  with kinase and ITAM phosphorylation.

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Figure 6-16 part 1 of 2
Aggregation of receptors which have associated
Src kinases may lead to kinase activation and
initiation of signaling
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Figure 6-3
Aggregation of receptors may lead to their
localization in membrane rafts where Src kinases
can initiate signaling
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CD4 and CD8 co-receptors bind to Lck and help
initiate signaling by delivering the kinase to
the cytoplasmic domains of the T cell receptor
following binding to MHC-peptide
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Y
PTKs
?
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Protein tyrosine kinases use adaptor proteins to
link antigen receptors to intracellular
phosphatidylinositol (PI) and MAP kinase pathways
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PTKs
adaptors
PI pathway
MAP kinase pathway
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Adaptor proteins have no catalytic activity, but
can provide binding sites which bring together
effector and target proteins to promote efficient
signal transduction
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ZAP-70 phosphorylates two adaptor molecules
Linker for Activated T cells (LAT) and SH2 domain
containing Leukocyte Protein (SLP-76)
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MAP kinase signal transduction pathway Guanine
nucleotide exchange factors (GEFs) activate small
G-proteins to initiate a sequence of kinase
phosphorylation events which culminate in
transcription factor activation
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Two different MAPK pathways are involved in
lymphocyte activation
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The transmembrane adaptor LAT recruits SOS, a GTP
exchange factor, to the membrane where it
activates Ras and initiates the (ERK) MAP kinase
pathway
GRB2
LAT
MEK
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Phosphatidylinositol signaling pathway
Phospholipase C activity generates second
messengers, inositol trisphosphate (IP3) and
diacylglycerol (DAG) which increase levels of
intracellular calcium and activate Protein kinase
C (PKC).
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The LAT and SLP-76 adaptors co-localize PLCg and
the Tec family kinase ITK. Activation of PLCg by
ITK induces cleavage of PIP2 to DAG and IP3.
DAG
PLCg1
IP3
ITK
LAT
P
SLP-76
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Like the LAT adaptor, Phosphatidylinositol
3kinase (PI3-K) is able to induce the membrane
recruitment. PI3-K produces PIP3 leading to the
localized membrane binding of PH domain
containing proteins.
PIP2
PIP3
ATP
PH domain containing proteins
PI3Kinase
Vav
PLC
BTK
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The B cell co-receptor enhances B cell
activation in response to antigens recognized by
the BCR and complement receptor CR2.
Co-aggregation of the BCR and CD19 results in Src
kinase phosphorylation of CD19.
PI 3-K binds to phosphorylated CD19 and generates
PIP3, leading to the membrane recruitment of the
G-protein exchange factor Vav.
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Regulation of gene expression through increased
transcription factor activity
NFAT nuclear localization regulated by
calcium-activated phosphatase AP-1 expression
and activity regulated by MAPK pathways NFkB
nuclear localization regulated by degradation
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The NFAT transcription factor is normally
phosphorylated and sequestered in the cytosol.
The PI pathway induces calcium influx which
activates Calcineurin phosphatase activity and
promotes nuclear translocation of the NFAT
transcription factor.
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MAP kinase pathways increase AP-1 dependent
transcription by increasing expression of the Fos
subunit, and by increasing activity of the Jun
subunit
Fos
-P
-P
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Stimulated antigen receptors utilize tyrosine
kinases to induce intracellular signaling
pathways leading to transcription factor
activation and the induction of cell growth and
differentiation.
Y
PTKs
adaptors
PI pathway
MAP kinase pathways
Interleukin-2, and effector functions
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Interaction domains found in signaling proteins
Domain
Ligand
Phosphotyrosine
SH2
Proline-rich sequences
SH3
Phosphatidylinositol Triphosphate (PIP3)
PH