part 8 Flashcards
what is traf6
an adapter protein that involved in cytoplasmic RNA and DNA signaling, especially for cytokine or interferon production.
in TLRs, what ubiquination of traf6 entail
a scaffold protein is produced
what do the receptors of the cell determine
physiology of the cell
what are the two main target of cell signaling
Go straight to the nucleus; gene expression and cell division
Cytoskeleton
properties of the nucleus target
For gene expression: cell differentiation.
Gene expression allows for new protein productions
properties of targeting the cytoskeleton
Motility, phagocytosis, vesicle production.
Change shape, cell size, motility.
what is the function of kinases
they phosphorylate substrates
In other words, it adds phosphate groups and causes a conformational change of enzyme (activation)
what kind of receptor domains are present in kinase receptor classes
a kinase domain
what does a kinase domain do
Ligand binding dimerizes the receptor, activating the kinases, which phosphorylate each other.
The activated kinases phosphorylate downstream substrates.
what is another way kinases are associated with receptors
through noncovalent kinase association
what happens when kinases are covalently associated with each other
Ligand binding dimerizes receptors, activating associated kinases, which phosphorylates each other.
Activated kinases phosphorylate downstream substrates.
what is signaling strength dependent on
the interaction between the receptors and the ligand.
receptor factors in regards to signal strength
Threshold (how many receptors are needed)
Amplitude (strength)
Duration
Regulation (on and off switches)
ligand factors in regards to signal strength
Affinity (how well is the ligand binding)
Spatial abundance (how many ligands and where is it located)
Temporal abundance
what type of kinase is found in cytokine signaling
Ser/Thr kinases, which phosphorylate only at the serine or threonine amino acids.
what kinase is found in T and B cell signaling
Tyrosine kinase (rare), which phosphorylates at the tyrosine amino acid.
what is a protein domain
the phosphorylation recognition site of the recognizing protein for a ligand class.
what is an adapter protein
The protein that brings different proteins together (multiple bound protein receptors)
what other properties of ligands must be accounted for binding
Spacing between ligand and proteins must be correct
how is the signaling pathway started
Scaffold protein is phosphorylated by a kinase, and recruits signaling proteins that bind.
All proteins bound have the same domain type of binding (SH2, 3, etc.)
The adapter Grb2 binds to the signaling protein Sos via its SH3 domains.
Activated receptor becomes tyrosine phosphorylated.
Grb2 binds to phosphotyrosine via SH2, bringing Sos to the receptor.
what is the Ras protein
has the ability to induce cell proliferation.
When mutated, it is known to cause cancer (doesn’t know how to turn itself off).
It is an oncogene.
when is Ras activated/inactivated
Active when bound to GTP
Inactive when bound to GDP
what happens when Ras is activated by GTP
signals for cell proliferation
what is a GEF
guanine-nucleotide exchange factors
swaps GDP with GTP
what is the relationship between GEF and Ras
GEFs swaps GDP with GTP, which activates Ras.
what is an example of a GEF
Sos
what turns off the Ras/switches GTP for GDP
GAPs
what is a permanent way to turn of cell signaling
degradation of proteins
how is the degredation of proteins started
Phosphorylated substrates are dephosphorylated.
how are proteins tagged for degradation
ubiquitin
K48 is an area where long chains of ubiquitin are attached to the targeted
protein
where are ubiquinated proteins sent to be degraded
degradation in proteasome
Can also be degraded in the lysosome
how is ubiquination related to both activation and deactivation
Ubiquitination can activate by creating scaffold or deactivate by tagging proteins for degradation by proteasome.
what is the proteins present in the amplification of kinases
Raf > Mek > Erk
MAPK > MAPKK > MAPKKK
what does signaling’s second messenger
calcium
how does calcium relate to cell signaling/as a second messenger
Calcium rapidly diffuses throughout the cell and induces conformational changes in calmodulin.
When calmodulin is bound to calcium, it changes shape, which allows for effector proteins to bind to it.
Calcium is also found in the synaptic cleft when neurotransmitters are released (changes charge) and acts as the second messenger for skeletal/muscle movement.
what are the CD3 prrotein
located adjacent to the TCR on both sides, recognition of antigens and subsequent signal transduction and activation of immunocompetent T lymphocytes.
what is the structure of CD3s
ITAMs are connected to CD3
made of epsilon:delta and gamma:epsilon proteins
what do ITAMs phosphorylate
tyrosine
what other cells have ITAMs
APCs that have an Fc receptors (monocytes, macrophages, neutrophils, and Mast cells)
what do B cells have to help with signaling
Igbeta and Igalpha next to the membrane-bound antibody.
Igb and Iga have ITAMs, too
what is the ratio of tyrosine to ITAM
2 tyrosines for every ITAM
how many TCRs need to be bound for CD4s to activate
about 50
how many TCRs do T cells have
about 10,000 that bind with APCs
how many TCRs bound for CD8s to activate
a little under 50
what is clustering
in T cells, you can bind antibodies to CD3 in order to activate the T cell falsely (lab experiment)
what is the function of CD28
costimulatory receptor
brings in a survival signal
what binds to CD28
APCs with B7
what abilities do BCR and TCRs not have
cell signaling capabilities
what do T cells depend on for cell signaling
CD3 complex (epsilon, delta, zeta, and gamma chains); dimers.
what is the structure of the CD3 complex; what binds to what
TCR alpha chain binds to epsilon:delta and zeta dimers.
TCR beta chain binds to gamma:epsilon and zeta dimers.
what do B cells rely on for signaling
Ig alpha and beta
what are the interactions of the B and T cell accessories
Interactions of accessories are through transmembrane region
what interactions do TCRs have
charges
what interactions do BCRs have
hydrophobic interactions/regions
what is needed for T cell binding
MHC II:Ag
TCR
CD45 receptor (Lck)
ITAMs
CD3 complex dimers
what is the first step of T cell signaling
TCR:MHCII binding brings in CD28 and 45
what does CD45 bring in
Lck by dephosphorylation
what is Lck
a tyrosine kinase
what are the different versions of CD45
RO and RA
what is the second step of T cell signaling
Lck phosphorylates ITAMs, which brings in Zap70
what does zap70 phosphorylate
LAT/SLP76, which brings in scaffolding proteins
what are the zap70 scaffolding proteins
LAT, SLP76, GADs
These proteins are a complex.
LAT is a protein that is attached to the membrane intracellularly.
what does the assembled scaffolding proteins bring in
PLC-gamma
what is the third step of T cell signaling
Lck also phosphorylates CD28, bringing in PI3K
what is the fourth step of T cell signaling
PI3K phosphorylates PIP2 to 3
what does PIP3 attract
3 kinases:
Itk
PDK
Atk
what happens to PIP2
it is cleaved by PLC-gamma into IP3 and DAG
what does IP3 do
raises Ca from ER, which binds to calmodulin. calmodulin is P into calcineuron phosphatase enzyme
what does the calcineuron phosphatase activate
the NFAT tx factor (IL2 and cell differentiation)
what does DAG do
DAG activates GAD (Ras activator) and TRAF6.
TRAF6 is recruited by CARMA1, and activation leads to NF-kappabeta transcription factor
GAD will also activate transcription factors later.
what is the most important gene that is activated during T cell activation
IL2
what is the first signal of TCA
TCR
second signal of TCA
CD28
signal 3 of TCA
cytokines; chemokines from APC being bound to T cell receptors
what do all signals come from in TCA
the APC
when is IFN secreted
by virus-infected cells to neighboring cells
Modulates activation and specific infection through IFN
What the cell should do in order to fight the infection.
what is IL2
a survival and growth ligand that binds to the IL-2 receptor.
what needs to happen in order for T cells to activate
there must be a threshold of MHC:Ag:TCR that is met
There is many different peptides/MHCs on the APC
what is NF kappa beta
a transcription factor protein complexes induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines, and also participates in inflammasome regulation
how is Lck regulated
Lck is regulated CD45, which is a phosphatase (removes phosphates on Lck)
what kinse deactivates Lck
Csk is a kinase that phosphorylates Lck, which deactivates Lck
what are the three transcription factors that result from IP3 and DAG
NFAT (IL-2)
AP-1 (proliferation, differentiation and cell death)
TRAF-6 (E3 ligase) to NF-KB (inflammatory responses)
what needs to happen simultaneously for IL2 to be produced
All three transcription factors need to be made and activated at the same time in order to get IL-2 production.
in B cell activation, what is similar to Lck
Fyn
Blk
Lyn
what is like the CD3;zeta chains in BCA
Ig alpha and beta
what is Zap70 in BCA
Syk
what is the B cells CD4 and 8
CD19, 21, and 81
what is the PLC-gamma in BCA
Btk
how is cell signaling stopped
To turn off, a signal will be sent to express CTLA-4 on the surface.
CTLA-4 outcompetes CD28 for B7, and clusters together.
what is an alternative off switch to CTLA4
PD1
what do naive cells require that memory cells don’t
Memory cells do not require CD28 activation, while naive cells absolutely do.
what does B7 costimulate with
CD28
