JAK-STAT signalling Flashcards
explain the JAK-STAT signalling
- composed of a) transmembrane protein b) JAK at the intracellular domain of the receptor c) STAT ( a transcription factor) and d) Ligand (“tins” EPO, prolactin, thrombopoeitin, leptin , “ters” interferons, interleukins, GM-CSF???
- ligand cause oligomerization of receptor
- When ligand is bound to the receptor, oligomerization induce intracellular activation
- JAK will transautophosphorylate when it is brought in close proximity to one another following oligomerization
- activated JAK will phosphorylate the tyrosine residues on the receptor and also STAT
- STAT will homo/heteroDIMERise trough SH2 domain
- STAT enter the nucleus and bind to GAS element ( Gamma Activated Sequence)
- increase Transcription
how many JAKs and STATs are there?
4 JAKs and 7 STATS
JAK1,2,3, tyk2
stat 1,2,3,4,5A,5B,6
What does JAK-STAT signalling pathway does
- regulate eythropoesis
- signalling mechanism for cytokines and growth factors
*
what are the receptors for these cytokines
a) Erythropoeitin,
b) thrombopoetin, and
c) G-CSF
Erythropoeitin -> EPO - R
Thrombopoeitin -> cMPL (or TPO-R)
G-CSF -> G-CSF R
what are the phenotype of deletion mutation of some cytokine receptos?
- embyronic lethal, failure of definitive eythropoeisis
- cMPL»_space; reduced hematopoeitic stem cells, reduces megakaryocytes and thrombocytopenia
- G-CSF»_space; chronic neutropenia, impaird neutrophil mobility
What is gp130
- GLYCOPROTEIN 130
- a transmembrane domain
- founding member for all cytokine receptor
- activate several pathways
a) JAK-STAT
b) RAS , ERK
describe the activation of gp130
- ligand bound to receptor such as IL6 binds to IL6R or (IL11) or (Mosm-osmrB) or (LIF-LIFR)
- then they will bind to gp130 forming a complex ( consisting fo IL-6R, IL6 and gp130)
- b this complex will dimerize into a hexameric structure and induce downstream signalling
- gp130 does not have an intrinsic kinase activity, thus must be activated by phospharylation on the tyrosine residue by other protein
- phosphorylation recruits and activate JAK and STAT via phosphorylation
5.
can a IL-6Ralpha induce donwstream signalling?
no. IL6Ra is not a signalling receptor, must bound to gp130
Describe the IL-6, IL-6R and gp130 complex
- IL-6 cytokine have 3 binding site for IL-6R(1) and gp130(2)
- following binding, complexes are internalised
describe the intracellular structures of beta receptors
- have box1 and box 2 ( sometimes box3 domains)
* places where JAK binds
Explain hop tuml mutation
- mutation in drosophila
- tuml - tumor lethal
- phenotype : identical to wasp infected larvae
- temperature sensitive
- @ 17c = more blood cells, less lamellocyte
- @ 25c = more lamellocytes, but less total blood count
Explain hop tuml mutation
- mutation in drosophila
- tuml - tumor lethal
- phenotype : identical to wasp infected larvae
- temperature sensitive
- @ 17c = more blood cells, less lamellocyte
- @ 25c = more lamellocytes, but less total blood count
What is the feature of temperature sensitive mutation in HOP tuml?
- @ 17c = more blood cells, less lamellocyte
* @ 25c = more lamellocytes, but less total blood count
gain of function of JAK
increase lamellocytes
What is MPN
myeloproliferative neoplasms
classic examples
MF, ET, PV
MF - scar tissue ET - increased platelet - blood clotting PV - polycythemia vera increased red blood cells enlarged spleen
What is MF
primary myelofibrosis
- chronic blood cancer
- bone marrow impacted by scarring
- enlarged spleen, trying to make up blood making for bone marrow
- can be obtain from progression from pv and et
what is ET
Essential Thrombocythemia
- Blood malignancy with too many platelet
- problem with blood clot
What is PV
polycythemia vera
- increased RED BLOOD CELL
- also increase wbc and platelet
- enlarged spleen
James 2004 in Nature
Jak2 mutation»_space; constitutive signalling»_space; polycythemia vera
difference between the wt and gain of function mutation of jak2
JH1 = kinase domain»_space; switching jakstat signalling pathway on
JH2 = pseudo-kinase domain»_space; looks like a kinase domain but its not!
JH2 negatively regulate JH1
mutation in JH2 , reduced negative regulate, less inhibiting the JH1, so increased activity of JH1
Describe mutation found in MPL
MPL/c mpl / TPO r
ligand = thrombopoeitin
in normal Mpl
- dimerisation of mpl receptor is brought about by binding to TPO
- Dimerisation causes the intracellular domain to be closer together and JAK2 can be phosphorylated ( and the normal downstream signalling)
in mutation
- dimerisation is TPO independent, no need for TPO
- dimerisation of MPL is sufficient to activate the receptor
- this is caused by a mutation that adds cysteine residues, to form disulphide bridges
- -different from domeless–
PML triggers megakaryocytes differentiation and platelet production
What is CALR
a chaperone that lives in the ER
How does CAL R mutation cause MPN?
- frameshift mutation
- +1 frame shift mutation
- causes the whole sequence to be read differently
- producing a completely different peptide sequence
- result in novel protein to be prodcuced
mutation in which gene causes increased in JAK STAT pathway>
- JAK2 > gain of fx in JH2 domain
- MPL > gain of fx in transmembrane domain
- CAL R > frameshift mutation that output novel protein
