Cytokine receptors and cytokine signalling Flashcards
What is a cytokine?
Any class of immunoregulatory proteins that are secreted by cells especially of the immune system
What do cytokines do?
Modulate the behaviour of cells
Physiological events such as hematopoiesis, immunity and inflammation
What are the four major categories of cytokines?
TNF family, chemokine family, interferon family, interleukin family
What is the function of interferons?
Anti-viral activity
What is the function of TNFs (Tumour Necrosis Factor)
A pro-inflammatory cytokine
What is the function of chemokines?
Control and direct cell migration
What is the function of interleukins?
They have various functions
What type of receptors are the majority of cytokines?
Kinase-linked receptors
True or false?
Unlike other kinase-linked receptors, cytokine receptors dont possess intrinsic catalytic activity
True
What class of cytokine receptors comprise the majority of kinase-linked cytokine receptors?
Class 1 and 2
What region forms the basis of all cytokine receptor structures?
The cytokine homology region (CHR)
Where does cytokine binding occur and what does it lead to?
In the dimerization/oligomerization of receptors which leads to the juxtapositioning of JAKs.
Where do JAKs phosphorylate cytokine subunits?
Conserved tyrosine sites
What can occur on phosphorylated receptor sites?
Docking sites that permits binding or STAT transcription factors
Once phosphorylated, STAT proteins change conformation and form high affinity homo/hetero-dimers via the interaction of what?
Interaction of SH2 domain of one STAT molecule with the tyrosine phosphorylated residue of another
How are the dimerized STATs able to translocate into the nucleus and regulate gene expression?
Through the binding to TTC(N)2-4GAA consensus DNA binding elements in STAT-target genes
What is the function of the STA-regulated genes, SOCS proteins?
They negatively feedback on the JAK-STAT signalling pathway to terminate cytokine receptor signalling (Inhibitors of cytokine receptor signalling)
What are the eight known family members of SOCS?
SOCS1-SOCS7 and CIS
What is an example of a cytokine receptor that is produced by antigen-activated T cells?
Interleukin-2 receptor (IL-2R)
What type of affinity and signal do Naiive T cells have?
Intermediate affinity complex
Weak signal
What type of affinity and signal do Activated T cells have?
High affinity complex
Strong signal
Describe the 3 step pathway of the IL-2 receptor
1) IL-2 receptor activates several intracellular signal transduction pathways
2) JAK1/3 -> STAT5 pathway
3) Cell cycle entry and proliferation of activated T cells
Explain the link of IL-2 and the STAT activated
IL-2 activates more STAT5 than STAT3 and more STAT3 than STAT1
What does IL-2R/JAK/STAT5 all have in common with each other?
Controls Myc and cyclin D expression in activated T cells which leads to T cell growth and cell cycle entry
What is JAK1/3 inhibition effective in doing?
Effective at amerliorating cytokine-induced disease in vivo
What is the function of Granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR)
A multifunctional cytokine that regulates inflammatory responses, including emergency responses in the bone marrow
What is recombinant GM-CSF clinically used for?
To accelerate white blood cell recovery following autologous bone marrow transplantation
What does GM-CSF signal via?
Via a multimeric cytokine receptor complex that contains a shared receptor subunit, the common beta chain
What two subunits is GM-CSF composed of?
heterodimer composed of an alpha subunit (GMRa) and beta c subunit
What is the beta c subunit also involved in?
Signal transduction through its interaction with JAK2
What are the cytoplasmic domains of both GMRa and Bc essential for?
Receptor activation
What does the low-affinity receptor complex consist of?
GM-CSF bound to GMRa
What forms the high-affinity hexameric receptor complex?
Interaction of GM-CSF/GMRa with free (dimeric) Bc subunits
How are dodecamer (or higher-order) receptor complexes formed?
Form by lateral aggregation of hexameter complexes in the plasma membrane to form a fully competent signalling complex
What is able to dimerize and transphosphorylate within the dodecamer complex but not within the hexamer complex?
JAK2 associated with Bc (common beta chain) subunits
What does GM-CSF signal via?
Via a classical JAK2-STAT5 signalling pathway
What is hematopoiesis?
Formation of red blood cells in the bone marrow
What does JAK stand for and what are they?
Janus kinases
Family of intracellular tyrosine kinases
What does STAT stand for and how many family members?
Signal Transducers and Activators of Transcription
7 family members
How does an unphosphorylated STAT exist?
Antiparallel dimer in the cytoplasm where SH2 domains are far apart from each other
How does STAT exist when the JAK phosphorylates the tyrosine residue?
Induces a large rotation in the two subunits of the dimer and allows SH2 domains to come within close proximity of eachother
Now competent to binding with DNA
