CD 28 signaling
Induction of immune response requires T cells to receive two sets of signals from
antigen-presenting cells. The first signal is delivered via T-cell receptor complex
(TCR), while the second one proceeds via co-receptor
CD28. TCR and
CD28 are independent signaling units. However,
Cd28 amplifies signal triggered by TCR ligation .
CD28 is a
T-cell surface protein activated by interacting with the B-cell activation
antigens CD80 and CD86 .
In response to ligand activation, CD28 binds with the regulatory subunits of
phosphatidylinositol kinase 1 (PIK3R1A), adaptor proteins
GRB2 and GRB2-related adaptor protein
(GRAP2) and T cell-specific tyrosine kinase
ITK , .
Lck and Fyn are critical for
the CD28 co-stimulation. These kinases phosphorylate motifs
present in the cytoplasmic tail of CD28, thus enabling it to bind p85 subunit of
PI3K and GRB2 .
Lck and Fyn also phosphorylate
and consequently activate Itk and
Vav-1 respectively , .
CB28 binds with SLP-76 via
adaptor proteins GRB2 and
GRAP2. SLP-76 recruits
VAV-1, linking CD28 to
VAV effectors. Mechanism of
Vav-1 activation upon CD28
ligation is unclear. Putatively, TCR selectively induces
ZAP-70 activation, followed by phosphorylation of the
scaffold proteins LAT and
SLP-76 . LAT,
in turn, can bind to the SLP-76 adaptor via GRB2 and GRAP .
Vav-1 exerts pleiotropic effects mediated by the Rho
family of guanosine triphosphatases (GTPases). Rac1 is a
target for VAV and participates in actin cytoskeletal
Additionally, VAV-1 regulates activity of
PLC-gamma 1 by facilitating availability of
PtdIns(4,5)P2, the PLC-gamma 1
substrate via stimulation of PIP-5 kinase, a Rac1 downstream
Itk also phosphorylates and activates
PLC-gamma 1 .
The activated PCL-gamma 1 is responsible for synthesis of
second messengers Diacylglycerol (DAG) and Inositol
1,4,5-triphosphate (IP3) by cleaving
Phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2) at the
plasma membrane. DAG activates a number of proteins,
including various isoforms of protein kinase C (PKC).
PKC-theta activates kinase IKK,
which phosphorylates serine residues on I-kappa-B proteins,
thus marking them for destruction via ubiquitination, and, thereby, enabling activation
of the NF-kappa-B complex .
IP3 binds IP3 Receptor
(IP3R), which is localized primarily on the endoplasmic reticulum where it
stimulates release of calcium from intracellular stores. Calcium-bound
Calmodulin associates with and activates serine/threonine
NF-AT family of transcription factors leading to theirs
translocation to the nucleus .
Activated PI3K converts
PtdIns(4,5)P2 into Phosphatidylinositol 3,4,5-triphosphate
CD28 ligation stimulates generation of
PtdIns(3,4,5)P3 associates with the inner face of
the plasma membrane promoting recruitment of proteins with pleckstrin homology (PH)
domains, such as ITK, VAV1,
and Akt . Akt blocks Glycogen synthase
kinase-3 (GSK-3), which phosphorilates
NF-AT and, thereby, prevents its nuclear translocation
Additionally, CD28 activates
JNK cascade via VAV-1
activation. VAV-1 activates
Rac1 and CDC24, which activate
JNK via MEKK1 and
MKK4/7. Activated JNK
phosphorylates transcription factors such as
JUN, thereby activating AP1 complex, involved in regulation
of cell proliferation .
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