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signal transduction for T cell activation
cmbm exam III
30
Chemistry
Graduate
01/16/2010

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Term
do the alpha and beta chains of the TCR have cytoplasmic domains? how are signals from antigen sent intracellularly?
Definition
no, however the zeta and CD3 molecules have cytosolic domains
Term
what are ITAMs? what do they do?
Definition
immunoreceptor tyrosine based activation motifs - common elements in the cytosolic domain of the signaling proteins, (zeta and CD3). these are sites for regulatory tyrosine phosphorylation, (both positive+negative)
Term
what are lck, (p56lck - src family), and fyn, (p59fyn - src family), and ZAP70, (zeta associated protein)? what do they do?
Definition
protein tyrosine kinases that phosphorylate tyrosine residues, (ransfers a terminal phosphate group from ATP to the hydroxyl group of a tyrosine). they alter protein-protein binding and alter enzymatic activity.
Term
what does p56lck do in a resting, (no antigen bound) T cell? is its ITAM phosphorylated?
Definition
nothing, it is phosphorylated, and thus inactivated. the zeta chain/C3 ITAMs however are NOT phosphorylated
Term
what happens to p56lck when antigen binds to the TCR?
Definition
CD4 binds to the invariant region of Class II MHC and simultaneously, CD45 dephosphorylates and activates p56lck
Term
what is p56lck? what does it do when CD45 activates it?
Definition
p56lck is a tyrosine kinase, and when CD45 activates p56, it phosphorylates ITAMs on CD3 and zeta chains
Term
what does p59fyn do relative to p56lck?
Definition
p59fyn is a cytoplasmic tyrosine kinase, part of the src family and is is partially redundant to p56lck's activity. the main difference is that p59fyn is found in association with TCR, even in resting cells
Term
how is ZAP-70 activated? do they bind anywhere?
Definition
ZAP-70 is phosphorylated and activated, (presumably by p56lck/p59fyn). they also bind to the phosphorylated ITAMs on CD3/zeta chain
Term
what does ZAP-70 do?
Definition
ZAP-70, once phosphorylated, is a tyrosine kinase that phosphorylates the gamma-1 subunit of phospholipase C and activates Ras, (G protein)
Term
what does phospholipase C do when ZAP-70 activates it?
Definition
phospholipase C cleaves PIP2 into DAG and IP3, (diacylglycerol and inositol trisphosphate).
Term
what does IP3 do when it is cleaved from PIP2 by phosphorylated phospholipase C, (along with DAG)?
Definition
IP3 opens a calcium channel to allow its release from the ER in the first wave of Ca++ release. IP3 then opens a pore in the cell membrane, creating the second wave of Ca++, this time extracellular
Term
what do the Ca++ influx, (mediated by IP3) and DAG do
Definition
Ca++ and DAG activate protein kinase C, (PKC)
Term
what does protein kinase C do once activated by Ca++ and DAG?
Definition
PKC phosphorylates negative regulatory peptide, IkappaB, thus activating NFkappaB
Term
what does NFkappaB do once activated by protein kinase A?
Definition
NFkappaB is a transcriptional factor ultimately activating changing the gene expression and producing CD40L (CD40 ligand), IL-2 (interleukin 2), IL-2R (p55 alpha chain of the IL-2 receptor and upregulation of the beta chain)
Term
other than activating protein kinase C, what other role does Ca++ play when lead to influx via IP3?
Definition
Ca++ complexes with calmodulin
Term
what does calmodulin do when complexed with Ca++?
Definition
calcineurin, (serine/threonine phosphatase), is activated which dephosphorylates NFAT, thus activating it
Term
what does NFAT do when activated?
Definition
NFAT is a transcriptional factor ultimately activating changing the gene expression and producing CD40L (CD40 ligand), IL-2 (interleukin 2), IL-2R (p55 alpha chain of the IL-2 receptor and upregulation of the beta chain)
Term
are there immunosuppressive drugs that target NFAT activation? how do they work?
Definition
cyclosporine A complexes with cyclophilin and FK506, (tacrolimus) complexes with FKBP. both of these complexes INHIBIT calcineurin. this blocks NFAT, which blocks IL2 production, which shuts immune responses down because you don’t get T cell expansion
Term
other than NFkappaB and NFAT, what is the third transcription factor activated in T cell signaling? what is the first step in it's activation?
Definition
AP1, Ras has to be activated by ZAP-70
Term
what is Ras?
Definition
Ras is a GTP binding protein, (inactive when GDP is bound, activated by replacment with GTP by a GEF- guanine exchange factor)
Term
how does ZAP-70 activate Ras?
Definition
ZAP-70 is a protein tyrosine kinase that hooks up with adaptor proteins, (SH2, SH3 domains), that hook up with a GEF that replaces the GDP on inactive Ras with GTP, thus activating it
Term
what does Ras do once activated?
Definition
Ras binds to a MAP, (mitogen activated protein), kinase called Raf
Term
what does Raf do?
Definition
Raf, once activated by Ras, sets a MAP kinase cascade in motion that phosphoylates Elk 1
Term
what does Elk 1 do once activated by Raf?
Definition
Elk is a transcriptional factor that regulates the transcription of cfos
Term
what does cfos transcription by Elk1 do?
Definition
fos the only factor we will talk about today that has to be synthesized de novo, and once it is, it forms a complex with cytosolic jun, creating the AP1 transcriptional complex
Term
where does jun come from?
Definition
cjun is a cytosolic transcription factor that is activated by phosphorylation by JNK kinase, (jun-n-terminal kinase) which is activated by a MAP kinase cascade regulated by Rac, (another G protein closely related to ras)
Term
what do jun and fos do once fully activated?
Definition
form AP-1 a transcription factor
Term
what does AP-1 do?
Definition
AP-1 is a transcriptional factor ultimately activating changing the gene expression and producing CD40L (CD40 ligand), IL-2 (interleukin 2), IL-2R (p55 alpha chain of the IL-2 receptor and upregulation of the beta chain)
Term
of the four T cell activation pathways, NFkappaB, NFAT, cfos, and jun, which can be targeted for immunosuppressive therapy?
Definition
NFAT, by cyclosporine and tacrolimus which shut down calcineurin
Term
what is mutated Ras associated with?
Definition
neoplastic transformation, due to mutated GTPase activity
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