T-Cell Receptor and Co-stimulatory Signaling (Homo sapiens)

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Description

The activation and translocation of transcription factors NFAT, AP-1 and NF-kappa-B via the co-stimulatory signaling cascade triggered by MHC peptide, B7 proteins and PD-L1. The activation of NFAT involves a Ca2+/calcineurin disruption of a massive RNA-protein complex prior to its translocation into the nucleus and ultimate transcription factor activity.

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Ontology Terms

 

Bibliography

  1. Takahashi K, Yan I, Haga H, Patel T; ''Long non-coding RNA in liver diseases.''; Hepatology, 2014 PubMed
  2. Srikanth S, Gwack Y; ''Orai1-NFAT signalling pathway triggered by T cell receptor stimulation.''; Mol Cells, 2013 PubMed

History

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CompareRevisionActionTimeUserComment
86147view18:56, 1 July 2016EgonwReplaced a mim-conversion with Arrow.
85336view16:14, 7 May 2016EgonwReplaced a mim-conversion with Arrow.
84987view19:00, 4 April 2016AlexanderPicoreplaced mim-conversion with mim-stimulation for activation event
84488view23:12, 25 February 2016KhanspersQuick edit to datanode annotation or property
79880view11:48, 23 April 2015Mkutmonuse labels and graphical lines in legend
75360view19:37, 20 May 2014KhanspersUpdated legend with graphical lines instead of interactions
75297view01:58, 16 May 2014AlexanderPicoCompleted xref and layout update
75296view01:33, 16 May 2014AlexanderPicoRestored missing/miscopied comments per datanode
75295view01:17, 16 May 2014AlexanderPicoWorking on xrefs and layout
75294view00:37, 16 May 2014AlexanderPicoAdded refs for lncRNA (NRON) and NFAT complex
75288view00:54, 14 May 2014AlexanderPicoAdded NRON-NFAT complex and some IDs
75287view00:22, 14 May 2014AlexanderPicoOntology Term : 'calcineurin signaling pathway' added !
75286view00:20, 14 May 2014AlexanderPicoOntology Term : 'Toll-like receptor signaling pathway' added !
75285view00:20, 14 May 2014AlexanderPicoOntology Term : 'nuclear factor of activated T-cells signaling pathway' added !
75284view00:17, 14 May 2014AlexanderPicoModified description
75274view22:12, 13 May 2014AlexanderPicoModified title
73828view19:55, 25 February 2014Mbrandonadded receptor ligands
73827view19:47, 25 February 2014MbrandonPeriodical save, work in progress
73813view21:16, 24 February 2014Mbrandonedited key
73812view21:12, 24 February 2014Mbrandonreduced model
73811view21:03, 24 February 2014MbrandonPeriodical save, work in progress
73810view20:59, 24 February 2014Mbrandonadded CD8
73809view20:53, 24 February 2014Mbrandonupdated key
73808view20:48, 24 February 2014Mbrandonstill reduced
73807view20:47, 24 February 2014Mbrandonreduced pathway
73806view20:43, 24 February 2014MbrandonPeriodical save, work in progress
73805view20:34, 24 February 2014MbrandonReduced pathway
73804view20:32, 24 February 2014MbrandonPeriodical save, work in progress
73803view20:22, 24 February 2014MbrandonPeriodical save, work in progress
73802view20:12, 24 February 2014MbrandonPeriodical save, work in progress
73801view20:02, 24 February 2014MbrandonPeriodical save, work in progress
73800view19:52, 24 February 2014MbrandonPeriodical save, work in progress
73799view19:44, 24 February 2014Mbrandonshortened AP-1 pathway
73798view19:39, 24 February 2014Mbrandonshortened NFkB pathway
73797view19:35, 24 February 2014Mbrandonmoved bcl
73796view19:22, 24 February 2014MbrandonPeriodical save, work in progress
73795view19:11, 24 February 2014MbrandonPeriodical save, work in progress
72813view22:16, 9 December 2013Khanspersadded cd28 xref
72748view18:50, 4 December 2013MbrandonPeriodical save, work in progress
72477view21:37, 17 November 2013MbrandonSpecify description
72476view19:29, 17 November 2013MbrandonPeriodical save, work in progress
72475view18:49, 17 November 2013Mbrandonchanged PP2A activity
72315view00:51, 1 November 2013Mbrandonfinished first draft
72314view00:47, 1 November 2013MbrandonPeriodical save, work in progress
72313view00:37, 1 November 2013MbrandonPeriodical save, work in progress
72312view00:27, 1 November 2013MbrandonPeriodical save, work in progress
72311view00:17, 1 November 2013MbrandonPeriodical save, work in progress
72310view00:07, 1 November 2013MbrandonPeriodical save, work in progress
72309view23:57, 31 October 2013MbrandonPeriodical save, work in progress
72306view21:26, 31 October 2013Mbrandonalmost done with skeleton

External references

Datanodes

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NameTypeDatabase referenceComment
AKT1GeneProduct207 (Entrez Gene) Akt is a serine/threonine-specific protein kinase that plays a key role in many cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. Akt is recruited to the membrane by PIP3. Here Akt can be activated / phosphorylated (indirectly) by P13K and can then phosphorylate a variety of downstream pathways. Noteably, Akt promotes cell survival by inhibiting the cell death pathway and stimulates cell metabolism by increasing the utilization of glucose.
AP-1 ProteinA heterodimeric protein composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families
B7-1/ B7-2Complex
Bcl-xLProteinBcl-xL is a transmembrane protein in the mitochondria. It is a anti-apoptosis protein because it prevents release of cytochrome c from the mitochondria.
CD28GeneProduct940 (Entrez Gene) CD28 is a co-stimulatory surface receptor. It bind B7-1 and B7-2. After CD28 binds its ligand, it is phosphorylated by Lck. The effect of this phosphorylation activates P13K to generate PIP3 which recruits Itk to the cell membrane where Lck can phosphorylate it. Then Itk-P can recruit PLC-g
CD8AGeneProduct925 (Entrez Gene) CD8 co-receptor - alpha subunit
CD8BGeneProduct926 (Entrez Gene) CD8 co-receptor - beta subunit
CSNK1A1GeneProduct1452 (Entrez Gene)
CTLA4GeneProduct1493 (Entrez Gene) Expression is enhanced by IL-2.

Function is controlled largely by regulation of its surface expression. Initially CTLA-4 is in the intracellular membrane but moves to the cell surface after T-cell receptor signaling. When CTLA-4 cytoplasmic tail is NOT phosphorylated it binds to AP-2 (clathrin adapter molecule) and is removed from the surface. When the tail is phosphorylated AP-2 cannot bind and CTLA-4 is expressed on the surface. CTLA-4 competes with CD28 for B7 ligand, and it has a higher affinity of B7 in part because CTLA-4 binds B7 in a dimer.

CTLA-4 interfers with the formation of lipid rafts, TCR:ZAP70 microclusters, and central supramolecular activation complex.
Ca2+MetaboliteHMDB00464 (HMDB) Calcium ions are second messengers, small-molecule biochemical mediators. Calcium is released from the ER by IP3. It diffuses throughough the cell enabling the signal to activate a variety of taget proteins. A certain calcium ion concentration must be acheived before targets can be activated.
CalcineurinGeneProduct5530 (Entrez Gene) Calcineurin is a protein phosphatase that acts on NFAT.
CalmodulinProtein801 (Entrez Gene) Calmodulin is a calcium binding protein. Binding Ca ions induces a conformational change allowing calmodulin to bind to and regulate a variety of effector proteins.
DAGMetaboliteHMDB07223 (HMDB) Produced from PIP2 cleaveage by PLC-g. DAG is a membrane protein which can now recruit other signaling molecules to the membrane by serving as a binding target.
DYRK1AGeneProduct1859 (Entrez Gene)
DYRK2GeneProduct8445 (Entrez Gene)
ErkProteinErk is MAP kinase that is phosphorylated by MAPKK, Mek. SHP's and PP2A may also dephosphorylate Erk to some extent.
FYNGeneProduct2534 (Entrez Gene)
GSK3AGeneProduct2931 (Entrez Gene)
GSK3BGeneProduct2932 (Entrez Gene)
IKK complexGeneProduct2.7.11.10 (Enzyme Nomenclature) IKK is a complex of serine kinases. It phosphorylates IkB, stimulating IkB's ubiquitination which targets IkB for degradation by the proteasome.
IL2GeneProduct3558 (Entrez Gene) All three TFs (NFAT, AP-1, and NFkB) a needed to initiate IL-2 transcription.
IP3MetaboliteHMDB01059 (HMDB) IP3 is generated when PLC-g cleaves PIP2. IP3 is a second messanger that diffuses into the cytosol and binds to IP3 receptors on the ER therey opening calcium channels.
ITKProtein3702 (Entrez Gene) Itk is a membrane associated tryosine kinase. It binds to phosphorylated LAT and SLP-76 scafflods. From here is activates PLC-g by phosphorylation
IkBaProteinP25963 (Uniprot-TrEMBL) IkB is an inhibitory protein which when bound to NFkB holds it in an inactive state.
LAT / SLP-76 scaffold complexProteinLinker for Activation of T cells - LAT is a transmembrane scaffold protein. It can be phosphorylated by Zap-70. This scaffold includes LAT, SLP-76, Grb2, SOS, GADS
LCKGeneProduct3932 (Entrez Gene) Cytoplasmic tyrosine kinase - Lck in its inactive state is bound to CD4/CD8 cytoplasmic tail and it's terminal tyrosine is phosphorylated. Dephosphorylation of this amino acid (by tyrosine phosphotase CD45 -- CD4/CD8 binding its ligand) causes a conformations change in LcK and it becomes an active tyrosine kinase.

LcK is activated when the extracellular part of CD8 binds its (MHC:peptide) ligand. Lck is a Src family kinase that is constitutively expressed. It phosphorylates all TCR ITAMS.

Rephosphorylation of this carboxyl-terminal tyrosine by Csk returns Lck to the inactive state.

Basically, Lck is bound to CD8. When CD8 binds MHC:peptide, Lck gets activated and can phosphorylate nearby ITAMs.
MHC peptideComplex
NFAT1Protein4773 (Entrez Gene)
NFKB1GeneProduct4790 (Entrez Gene)
NRONGeneProductENSG00000253079 (Ensembl) NRON is a long non-coding RNA
P13KProteinP13K converts membrane lipid PIP2 to PIP3 by adding a phosphate. P13K activity is dependent upon CD28 co-stimulation because P13K can bind to phosphorylated ITIMs on CD28. PI3K can also bind ICOS
PD-L1Complex
PDCD1GeneProduct5133 (Entrez Gene) PD-1 is repressed by pro-inflammatry cytokines. It's ligand, PD-L1, is constitutively expressed on T-cells. PD-1 contains a ITIM (immunoreceptor tyrosine-based inhibitory motif) in its cytoplasmic tail. When this ITIM is phosphorylated, it recruits either of 2 inhibitory phosphatases called SHP
PDK1GeneProduct5163 (Entrez Gene) Phosphoinositide-dependent kinase-1: recruited to the membrane by docking at PIP3 and phosphorylates/activates Akt
PIP2MetaboliteHMDB10059 (HMDB) PIP2 is a membrane lipid.
PIP3MetaboliteHMDB10147 (HMDB) PIP3 is a membrane lipid generated from PIP2 by the enzyme P13K. PIP3 has a PH binding domain that can be recognized by PLC-g, Itk, and Atk.
PKC-aGeneProduct5578 (Entrez Gene)
PLCG1GeneProduct5335 (Entrez Gene) PLC-g is a phospholipase, a class of enzymes that cleave phospholipids just before the phosphate group.

PLC-g is initially brought to the plasma membrane by binding of its PH domain to membrane lipid PIP3. PLC-g then binds to LAT and SLP-76 and can be activated by Itk mediated phosphorylation.

PLC-g ultimately produces 3 different second messangers to activate 3 paths leading to different TFs that lead to IL-2 transcription
PTENProtein5728 (Entrez Gene) Phosphatase and tensin homolog - PTEN is constitutively expressed and is a PIP3 phosphatase.
Ras-GAPGeneProduct5921 (Entrez Gene) Ras-GAP rapidly downregulates the activity of Ras by converting its bound GTP to GDP
Ras-GDPProteinRas is a small G protein of GTPase. It is located in the membrane, and it acts as a molecular switch. It is inactive when bound to GDP, but becomes active when GDP is switched for GTP. Binding the GTP induces a conformational change in Ras thus enabling it to bind to and do other things.
Ras-GTPProteinRas is a small G protein of GTPase. It is located in the membrane, and it acts as a molecular switch. It is inactive when bound to GDP, but becomes active when GDP is switched for GTP. Binding the GTP induces a conformational change in Ras thus enabling it to bind to and do other things.
RasGRPGeneProduct10125 (Entrez Gene) RasGRP binds to DAG in the membrane where it can activate Ras
SHP1GeneProduct5777 (Entrez Gene) SHP-1/2 are tyrosine phosphatases. Here, SHP removes phosphates from PIP3 reverting it back to PIP2. (reverses the work of tyrosine kinase P13K) SHP is recruited to the PD-1 cytoplasmic tail when PD-1 ITIMs are phosphorylated.
TCRAGeneProduct6955 (Entrez Gene)
TCRBGeneProduct6957 (Entrez Gene)
ZAP70GeneProduct7535 (Entrez Gene) ZAP-70 is kinase that becomes activated after phosphorylation. It contains to tandem SH2 domains that bind to phosphorylated ITAMs on the TCR complex cytoplasmic tails.

It docks at the TCR (requires both ITAM positions to be phosphorylated), is then phosphorylated by Lck, and then recruits other signaling proteins.

Annotated Interactions

No annotated interactions

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