Flashcards in JAK STAT Deck (69)
In simple terms, what is the JAK/STAT signalling pathway
Transmembrane receptors have an intracellular domain that is associated with JAK (a kinase). Ligand mediated dimerisation creates a receptor/JAK complex causes activation of the complex, activating tyrosine kinase, phosphorylation of tyrosines in correct context recruits STATs (TFs) which are activated by tyrosine phosphorylation and dimerise. The STAT dimer translocates to the nucleus, bind to DNA and activate transcription
How many JAKs are there?
4: JAK1,2,3 and JAK type 2
How many STAT TFs are there?
What does the pathway do
Key role in immune system development - specifically the differentiation of naive T cells.
Also has a role in haematopoiesis
Which STATs are involved in differentiation of T helper and T regulatory cells?
STAT3,4,5 and 6
What somatic JAK mutation causes SCID
A somatic JAK3 mutation
Which JAK/STAT ligands have an anti inflammatory effect
IL-4, IL-5 and IL-10
Which JAK/STAT ligands have proinflammatory effects
INF-y, IL-2, IL-6 and IL-12
What is the role of the JAK/STAT pathway in haematopoiesis
HPCs undergo self-renewal throughout life, the process of maintaining and differentiating HPCs is controlled by JAK/STAT pathway ligands (Thrombopoietin and erythropoietin)
What is the result of an embryonic JAK2 KO mouse
Embryonic lethal due to the absence of erythropoiesis i.e. no red blood cells.
What is the result of a JAK2 gain of function mutation
Causes blood cancers - Polycythaemia, Primary Myelofibrosis, Essential thrombocythaemia
Which STATs are involved in erythropoiesis
5a and 5b
what is the result of an EPO receptor KO
Embryonic lethal due to an absence of erythropoiesis
What is the result of a thrombopoietin receptor KO (AKA c-MPL receptor)
Knockout is viable but has a reduced number of HPCs and require thrombopoietin for their maintenance.
What is thrombocytopenia
A condition where the individual has a low platelet blood count. Caused by a mutation in the TPOR
Which three receptors dimerise and function as homodimers
TPO-R, EPO-R and G-CSFR
Do JAK/STAT signalling components experience crosstalk and how was this investigated
Antibodies specific to STAT1 and STAT3 as well as their phosphorylated forms gives an indication of receptor activation - IL-6 is thought to activate STAT3 but also leads to some STAT1 activation
Conversely IFN-y is thought to activate STAT1 but leads to a small amount of STAT3 activation.
Oncostatin M (OSM) strongly activates both STAT1 and STAT3 alluding to cross talk
Why is JAK/STAT analysis difficult in vertebrates
Because of their complexity and compensatory mechanisms through cross talk.
Name three homologues of IL-6
IL-11, LIF (leukemia inhibitory factor), OSM (oncostatin M)
What is the role of the cytokine IL-6
Proinflammatory cytokine inducing an inflammatory response.
What is the structure of IL-6 and IL-6 like ligands
Comprise four long alpha helices (A, B, C, and D) which are arranged in a way that gives them an up-up-down-down topology.
Do ligands express crossover between the receptors they bind
Yes, carrying out the same biological processes.
How is specificity for an individual ligand inferred by the receptor
By a different combination of transmembrane receptors (one must be gp130 containing)
What are the two types of gp130 containing receptor complexes
gp130 heterodimerising with a short receptor monomer - an alpha receptor
Or a gp130 heterodimerising with a long receptor - a beta receptor
What is the difference between the alpha receptor and the beta receptor for IL-6 like ligands
The beta receptor monomers are capable of signalling as they posses the JAK binding domain, whereas the alpha monomers are not
Name two alpha monomers
Name two beta monomer signalling receptors
Why does the affinity for the IL-6 like ligands have to be extremely high to its receptor
Ligands are present in the blood at vanishingly small amounts
What event follows ligand binding
The receptor-ligand complex is rapidly internalised via cytoplasmic dileucine motifs on the beta receptors