Pathway Map Details
Immune response_CD28 signaling
Object list (links open in MetaCore):
VAV-1, PLC-gamma 1, MKK7
(MAP2K7), LAT, GSK3 beta, IKK-gamma, c-Jun, 126.96.36.199, Rac1, NF-kB, Bcl-XL, TCR alpha/beta, Calmodulin, PAK1, CD28, AKT(PKB), 188.8.131.52, I-kB, MEKK1(MAP3K1), IKK (cat), ITK, 184.108.40.206, ZAP70, PtdIns(3,4,5)P3, NF-AT2(NFATC1), Ca('2+) cytosol, Slp76, NF-AT, Ca('2+) endoplasmic reticulum lumen, IKK-beta, CD86, PI3K cat class IA, Fyn, JNK(MAPK8-10), 1-(1,2-diacyl-glycerol
inositol 4-phosphate, CD80, PIP5KI, PtdIns(4,5)P2,
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 remodeling.
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 element .
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 ( IP 3 ) 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 phosphatase Calcineurin. Calcineurin dephosphorylates 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 ( PtdIns(3,4,5)P 3 ) . CD28 ligation stimulates generation of PtdIns(3,4,5)P 3. PtdIns(3,4,5)P 3 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 .
- Michel F, Acuto O
CD28 costimulation: a source of Vav-1 for TCR signaling with the help of SLP-76? Science's STKE [electronic resource] : signal transduction knowledge environment. 2002 Aug 6;2002(144):PE35
- Slavik JM, Hutchcroft JE, Bierer BE
CD80 and CD86 are not equivalent in their ability to induce the tyrosine phosphorylation of CD28. The Journal of biological chemistry 1999 Jan 29;274(5):3116-24
- Marengere LE, Okkenhaug K, Clavreul A, Couez D, Gibson S, Mills GB, Mak TW, Rottapel R
The SH3 domain of Itk/Emt binds to proline-rich sequences in the cytoplasmic domain of the T cell costimulatory receptor CD28. Journal of immunology (Baltimore, Md. : 1950) 1997 Oct 1;159(7):3220-9
- Rudd CE, Raab M
Independent CD28 signaling via VAV and SLP-76: a model for in trans costimulation. Immunological reviews 2003 Apr;192:32-41
- Acuto O, Michel F
CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nature reviews. Immunology. 2003 Dec;3(12):939-51
- Michel F, Grimaud L, Tuosto L, Acuto O
Fyn and ZAP-70 are required for Vav phosphorylation in T cells stimulated by antigen-presenting cells. The Journal of biological chemistry 1998 Nov 27;273(48):31932-8
- Acuto O, Mise-Omata S, Mangino G, Michel F
Molecular modifiers of T cell antigen receptor triggering threshold: the mechanism of CD28 costimulatory receptor. Immunological reviews 2003 Apr;192:21-31
- Raab M, Pfister S, Rudd CE
CD28 signaling via VAV/SLP-76 adaptors: regulation of cytokine transcription independent of TCR ligation. Immunity 2001 Dec;15(6):921-33
- Bustelo XR
Vav proteins, adaptors and cell signaling. Oncogene 2001 Oct 1;20(44):6372-81
- Tan SL, Parker PJ
Emerging and diverse roles of protein kinase C in immune cell signalling. The Biochemical journal 2003 Dec 15;376(Pt 3):545-52
- Hogan PG, Chen L, Nardone J, Rao A
Transcriptional regulation by calcium, calcineurin, and NFAT. Genes & development 2003 Sep 15;17(18):2205-32
- Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
- Graef IA, Mermelstein PG, Stankunas K, Neilson JR, Deisseroth K, Tsien RW, Crabtree GR
L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature 1999 Oct 14;401(6754):703-8
- Rudd CE, Schneider H
Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nature reviews. Immunology. 2003 Jul;3(7):544-56