Cellular Signaling III: Growth Factors and Cytokines Flashcards
What is unique about the receptors of growth factors
About their structure and properties
These receptors are usually 2 molecules that undergo nucleation event when the ligand binds to them.
Regarding the properties these receptors have catalytic activity associated with in their intercellular transmembrane domain. These are tyrosine kinase domain which can p’s stuff
What receptor did he show us
EGF receptor
What happens when the EGF ligand binds to the receptor
It leads to autop’s or cross p’s so now the receptor has phosphate groups on themselves
What are the other protein associated with growth factor receptor
A GDP binding protein called RAS, an adapter called GRB2-SOS and then a cascade of myogen activated protein kinases
- RAF
- MEK
- ERK
Ultimately what happens is that the signal is transmitted from the receptor to the myogen activated protein receptors
How is the singal transmitted between the receptor and myogen activated proteins
Grb2 is binds to the phosphate group on the tyrosine kinase part of the receptor at one end and to the SOS at the other end
What is RAS
It is a small G protein
What happens next
SOS if a GEF so it makes RAS loose its GDP and then RAS binds to GTP. This leads to tha activation of MAP kinases.
These MAP kinases ps in turn so RAF gets ps then MEK gets ps and finally ERK get ps which leads to the formation of trasncription facts which then go to the nucleus and regulates trasncription
What are some of the other proteins similar to ERK that regulate TFs p’s
- ERK regulates TF for proliferation and differentiation
- JNK regulates TF for stress response
- p38 also does stress response and apoptosis
- ERK5 does proliferation, differentiation and development
Each of these responses are isolated from each other
What is similar and different between growth factors and cytokine receptors
Cytokine receptors are pretty much like growth factors (are 2 molecules, undergo nucleation) but they dont have tyrosine kinase activity.
However cytokine receptors are associated with catalytic kinases called JAK kinases
How are the cytokine receptors activated
Interferon ligand attaches itself to the receptor, this leads to nucleation, this leads to a conformational change in JAK, JAK p’s the intracellular domain of the receptor, this leads to the binding of STAT protein, STAT is also a TF, STAT then dimerizes and goes to the nucleus to regulate transcription
How is the production of iNOS regulated
By cytokines. It is the same mechanism as described before
How are the growth factor signals terminated
There are a bunch os phosphatases that run around and dep’s the catalytic site of the receptors and the MAP kinases. However this is not enough since RAS with GTP is still bound to RAF and we also have the ligand bound to the receptor.
So there are GAP proteins that bind to RAS and causes the GTP to form GDP and inactvate RAS.
The receptor itself can be internalized and made to dissciate from the ligand. Receptor can also be degraded.
How are cytokines inhibited
PIAS, it stands for protein inhibitor of activated STAT. It has a binding site for STAT dimer so it doesnt let STAT to go to the nucleus.
Then the SOCS kick in and they bind to the p’s groups on the intermembrane domain, inhibiting more STATs to bind to these sites..
Then SOCS also have ubiqutinylation ligase activity so it will put ubiquitin markers on JAK. This is then spit out of the receptor and chewed up by proteasome.
What is inflammatory bowel disease
It has several diseases in itself like Crohn’s disease and Ulcerative colitis. The UC there is overexpression of the interferon gamma and there are elevated levels of STAT1. This leads to overexpression of genes that make NO so people with this disease pour out alot of NO into their gut which causes them to have this disease.
What are myeloproliferative disorders
There is a mutation in the JAK causing the JAK to be active without the nucleation event without the ligand cytokine, it will p’s the receptor domain causing the STAT to bind to the domain. This leads to a pannel of disorders.