T cell receptor and co-stimulatory signaling (WP2583)
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. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP2583 CPTAC Assay Portal].
AuthorsMbrandon , Kristina Hanspers , Alex Pico , Martina Summer-Kutmon , Egon Willighagen , Andika Tan , and Eric Weitz
Discuss this pathway
- DNA methylation of ARHGAP30 is negatively associated with ARHGAP30 expression in lung adenocarcinoma, which reduces tumor immunity and is detrimental to patient survival (2021).
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OrganismsHomo sapiens ExRNA
Pathway Ontologycalcineurin signaling pathway Toll-like receptor signaling pathway nuclear factor of activated T-cells signaling pathway
Cell Type OntologyT cell
|PIP2 is a membrane lipid.
|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.
|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.
|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.
|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.
|PIP2 is a membrane lipid.
|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.
|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.
|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
|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.
|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.
|Ras-GAP rapidly downregulates the activity of Ras by converting its bound GTP to GDP
|RasGRP binds to DAG in the membrane where it can activate Ras
|All three TFs (NFAT, AP-1, and NFkB) a needed to initiate IL-2 transcription.
|Calcineurin is a protein phosphatase that acts on NFAT.
|IKK is a complex of serine kinases. It phosphorylates IkB, stimulating IkB's ubiquitination which targets IkB for degradation by the proteasome.
|Phosphoinositide-dependent kinase-1: recruited to the membrane by docking at PIP3 and phosphorylates/activates Akt
|NRON is a long non-coding RNA
|CD8 co-receptor - alpha subunit
|CD8 co-receptor - beta subunit
|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
|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.
|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
|Itk is a membrane associated tryosine kinase. It binds to phosphorylated LAT and SLP-76 scafflods. From here is activates PLC-g by phosphorylation
|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.
|IkB is an inhibitory protein which when bound to NFkB holds it in an inactive state.
|Phosphatase and tensin homolog - PTEN is constitutively expressed and is a PIP3 phosphatase.