Lecture 18: Cytokine & Chemokine Receptor Signalling Flashcards
the cytokine ____ is responsible for transmitting a signal into the cell upon binding the ligand
t
cytokine receptor signalling is achieved by _____ of proteins in the cytoplasm, which results in a rapid pattern of _____ in multiple proteins
phosphorylation; alterations
which 2 classes of cytokine recptors lack intrinsic tyrosine kinase domains?
class 1 and 2
what are the 2 types of protein kinases?
tyrosine and serine/threonine
which inactive protein tyrosine kinase is associated with the alpha chain of class 1 and 2 cytokine receptors?
Janus kinase (JAK)
t/f the JAK is present on the alpha chain of class 1 and 2 even when there is no ligand present
t
in the absence of _____, the JAK lacks protein tyrosine kinase activity
cytokine
cytokine binding to class 1 or 2 receptors induced the association of ______ and activation of _____
the 2 separate cytokine receptor subunits; JAKs
activated JAKs in class 1 & 2 create ____ sites where _____ and ____ transcription factors can bind
docking; signal transducers and activators of transcription (STAT)
how do the activated JAKs create a docking site for STAT?
by phosphorylation of specific tyrosine residues on teh receptors
what domain of STAT bind to the docking site on JAK?
SH2
what does the JAK do with the docked STAT?
phosphorylates it
after STAT have been phosphorylated by JAK, what happens to them?
they translocate to the nucleus as dimers to initiate transcription of specific genes
in the JAK/STAT pathway of class 1 & 2, what determines which genes are transcribed?
determined by which specific DNA sequences the STATS bind to in the promotor region of the gene
what adds specificity to the JAK/STAT pathway?
there are multiple JAKs and STATs acting in different permutations
the cell cytokine cross-regulation can be explained at the level of _____
intracellular signalling
the expression of transcription factor T-Bet drives the cell to ____ differentiation and suppresses the differentiation to ____ cells
TH1; TH2
expression of transcription factor GATA-3 promotes differentiation to ___ cells, but inhibits the differentiation to ____ cells
TH2; TH1
how can STAT heterodimerization be accomplished?
by simultaneous activation of different cytokine receptors that result in phosphorylation of different STATs
IL-6 results in what type of STAT?
STAT3
IFN-gamma results in what type of STAT?
STAT 1
when both IL-6 and IFN-gamma bind to receptors on the same cell, what STAT heterodimers can result?
STAT1/STAT3
the specificity of cytokine effect is due to what 3 factors?
- the particular JAK/STAT pathway
- STAT specific sequences in the promoter regions of genes
- fact that only certain genes can be activated in a particular cell type
t/f in any give cell type, only a subset of the potential target genes of a particular STAT may be permitted to be expressed
t
do chemokines signal the same mechanism as class 1 and 2?
no
chemokine receptors are coupled with ____ G proteins
large heterotrimeric
in chemokine receptor signalling, the signal transduction generates second messenger such as _____, _____, _____, ultimately inducing ____ and ____
Ras (MAPK), Rho, PLCBeta; AP-1 & NF-kappaB
it is now believed that chemokine receptors may be able to signal through JAK, including through ___ and ____, which seems contingent on the ____ of the receptors
PKC and JAK-STAT; dimerization (can be hetero or homo)
IL-1, TNK and IL-17 signal through a mechanism which involves _____ of multiple different proteins ultimately leading to activation of _____
phosphorylation; NF-kappaB
what is NF-kappaB?
nuclear factor kappa B, a heterodimer s
NF-kappaB is sequestered in the cytoplasm by _____
IkappaB
IkappaBalpha becomes phosphorylated by ____ and then becomes ubiquitinated, which targets it for ___
IKK (I kappaB kinase); destruction by the proteosome
liberated NFkappaB is free to translocate to the ____ where it has what function?
nucleus; directs transcription
the range of genes activated by NF-kappaB is wide and includes _____ and ______
cytokines/other mediators and adhesion molecules
NFkappaB signalling makes its own inhibitor, ____ which serves to stop signalling
IkappaBalpha
The IL1R1 receptors has an accessory peptide (____) which provides a signal after IL-1 binds
IL-1RAcP
what is the function of IL-1Ra?
blocks IL-1 from binding to the receptor
what is IL-1R2 and its role in IL-1 signalling?
it is a different polypeptide that is able to bind the IL-1R, but when IL-1 binds, it wont transmit a signal
the IL-1R2 receptor can circulate in the blood to prevent ____
IL-1 from binding to the actual IL-1 recptor (further inhibits IL-1 signalling)
kinases put ___ groups on other molecules
phosphate
STATs are _____ (direct vs indirect) transcription factors
direct
if the tyrosine is mutated, will the cytokine receptor still work?
no
what STAT drives the transcription of T-Bet?
STAT 4
IL-__ causes production of STAT__, which promotes the actions of what transcription factor?
4; 6; GATA3
whichever cytokine comes first (___ or ___) determines if the cell will be Th1 or Th2
IL-12 or IL-4
G proteins of chemokine receptors can signal to ___, which signals to NF-kappaB
phospholipase c
NFkB is known as the master regulator of _____ bc of the number of cells it acts on as a transcription regulator
inflammation
how does IkappaB inhibit the actions of NFkB?
prevents it from crossing the nucleus
what are MAP kinases?
signalling molecules that integrate stress signals to your cell
give an example of a MAP kinase derived from growth factors
ERK1/2
give an example of a MAP kinase derived from environmental stress
JNK1-3
give an example of a MAP kinase derived from inflammatory cytokines
p-38a-o
