Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
Metalloprotease
G-alpha
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Transporter
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
DNA
RNA
Compound
Inorganic ion
Predicted metabolite or user's structure
Reaction
Generic receptor
GPCR
Receptors with enzyme activity
Mitochondria
EPR
Golgi
Nucleus
Lysosome
Peroxisome
Cytoplasm
Extracellular

Normal process
Pathological process
Binding
Cleavage
Covalent modifications
Phosphorylation
Dephosphorylation
Transformation
Transport
Catalysis
Transcription regulation
MicroRNA binding
Competition
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Immune response CD28 signaling


Log In to Post A Comment

Immune response CD28 signaling

CD 28 signaling

Induction of immune response requires T cells to receive two sets of signals fromantigen-presenting cells. The first signal is delivered via T-cell receptor complex (TCR ), while the second one proceeds via co-receptor CD28. TCR andCD28 are independent signaling units. However, Cd28 amplifies signaltriggered by TCR ligation [1].

CD28 is a T-cell surface protein activated by interacting with the B-cellactivation antigens CD80 and CD86 [2].

In response to ligand activation, CD28 binds with the regulatory subunits ofphosphatidylinositol kinase 1 ( PIK3R1A ), adaptor proteins GRB2 andGRB2-related adaptor protein ( GRAP2 ) and T cell-specific tyrosine kinaseITK [3], [4].

Lck and Fyn are critical for the CD28 co-stimulation. Thesekinases phosphorylate motifs present in the cytoplasmic tail of CD28, thus enabling it tobind p85 subunit of PI3K and GRB2 [5]. Lck andFyn also phosphorylate and consequently activate Itk and Vav-1respectively [1], [6].

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 ofthe scaffold proteins LAT and SLP-76 [7]. LAT, inturn, can bind to the SLP-76 adaptor via GRB2 and GRAP [8].

Vav-1 exerts pleiotropic effects mediated by the Rho family of guanosinetriphosphatases (GTPases). Rac1 is a target for VAV and participates inactin cytoskeletal remodeling.

Additionally, VAV-1 regulates activity of PLC-gamma 1 by facilitatingavailability of PtdIns(4,5)P2, the PLC-gamma 1 substrate via stimulationof PIP-5 kinase, a Rac1 downstream element [9].

Itk also phosphorylates and activates PLC-gamma 1 [9].

The activated PCL-gamma 1 is responsible for synthesis of second messengersDiacylglycerol ( DAG ) and Inositol 1,4,5-triphosphate ( IP 3 )by cleaving Phosphatidylinositol 4,5 bisphosphate ( PtdIns(4,5)P2 ) at the plasmamembrane. DAG activates a number of proteins, including various isoforms ofprotein kinase C (PKC). PKC-theta activates kinase IKK, whichphosphorylates serine residues on I-kappa-B proteins, thus marking them fordestruction via ubiquitination, and, thereby, enabling activation of theNF-kappa-B complex [10].

IP3 binds IP3 Receptor (IP3R ), which is localized primarily on theendoplasmic reticulum where it stimulates release of calcium from intracellular stores.Calcium-bound Calmodulin associates with and activates serine/threoninephosphatase Calcineurin. Calcineurin dephosphorylates NF-AT familyof transcription factors leading to theirs translocation to the nucleus [11].

Activated PI3K converts PtdIns(4,5)P2 into Phosphatidylinositol3,4,5-triphosphate ( PtdIns(3,4,5)P 3 ) [12]. CD28ligation stimulates generation of PtdIns(3,4,5)P 3. PtdIns(3,4,5)P3 associates with the inner face of the plasma membrane promotingrecruitment of proteins with pleckstrin homology (PH) domains, such as ITK,VAV1, and Akt [4]. Akt blocks Glycogen synthase kinase-3 (GSK-3 ), which phosphorilates NF-AT and, thereby, prevents its nucleartranslocation [13].

Additionally, CD28 activates JNK cascade via VAV-1 activation.VAV-1 activates Rac1 and CDC24, which activate JNK viaMEKK1 and MKK4/7. Activated JNK phosphorylates transcriptionfactors such as JUN, thereby activating AP1 complex, involved in regulation ofcell proliferation [14].