Cytokine Receptors: Signalling and Function Flashcards
Cytokine
Any class of immunoregulatory proteins (such as interleukin or interferon) that are secreted by cells, especially of the immune system
What do cytokines do?
Control the function of other cells
What physiological processes do cytokines regulate
Hematopoiesis (formation of blood cell components)
Immunity (function of WBCs)
Inflammation
What are the four major categories of cytokines and their functions
Interferons: anti-viral activity
Tumour necrosis factors (TNF): inflammatory response
Chemokines: control and direct cell migration
Interleukins: various
What family of receptors do cytokines (mostly) signal through (receptor superfamily not cytokine receptor type)
kinase-linked, the receptor is non-catalytic, must activate intracellular kinases
What type of cytokine receptors do most cytokines bind
Type I/II
What type of cytokine receptors regulate JAK/STAT pathways
Type I/II
What is a JAK
Janus kinase, a tyrosine kinase that is pre-associated constitutively with the receptors of cytokine receptors
What happens when ligand binding occurs on an alpha-chain cytokine receptor subunit
Beta chain and associated JAKs are bought closer and phosphorylate each other, activating tyrosine residues on the intracellular tail
What is the cytokine homology region (CHR)
conserved “Bent elbow structure” of cytokine receptor ligand binding region, ligand binds the outside of the elbow
How is specificity achieved in cytokine receptors
The 3D structures associated with the cytokine homology domain
What is in the JAK family
JAK1, JAK2, JAK3, Tyk2
Explain the domains of a JAK
FERM containing the SH2 domain, psi kinase domain containing nucleotide binding site, kinase domain containing ATP binding site
What do phosphorylated tyrosine residues activate in class I/II kinase-linked cytokine receptors
STAT dimers, once phosphorylated STAT dimers assume an active dimer conformation
What do STAT dimers do when activated
the nucleus where it binds specific DNA specific
Which domain of cytokine receptor subunits serves as a docking site for STAT transcription factors
SH2 domain of receptor subunit
Explain SH2 domain sites, function and specificity
two binding sites: one for amino acid side chains which gives specificity to the interaction and one for binding phosphorylated tyrosine (phosphotyrosine/pY)
on what proteins are SH2 domains commonly found
adaptor proteins that aid in signal transduction of kinase linked receptors
How do STAT dimers form
once phosphorylated, STAT proteins change conformation and form high-affinity homo- and hetero-dimers via the interaction of the SH2 domain of one and the pY phosphorylated residue of the other
What are the signal transducers and activators of transcription family members
STAT1
STAT2
STAT3
STAT4
STAT5a/b
STAT6
what type of feedback loop do cytokine, JAK, STAT pathways mostly activate
negative
What mechanisms do suppressor of cytokine signalling (SOCS) proteins use to negatively regulate cytokine receptor signalling
- Inhibition of JAK signalling by binding the tyrosine phosphorylated residue in the receptor tail, preventing JAK binding. (can do this as they have an SH2 domain)
- bind and directly inhibit JAKs
- SOCS box domain of SOCS bind ubiquitin ligases and recruits ubiquitin causing degradation of bound protein
why do SOCS need fine control
too little inhibition of cytokine signalling means hyperactivity of pathways
too much inhibition of cytokine signalling means autoimmune disease - no immune response
Where is Interleukin-2 (IL-2) produced and what is its function
Produced by antigen-activated cells and it acts as a major growth factor/mitogen for antigen-activated T cells
In what manner does IL-2 function (_____crine)
Autocrine and paracrine
Describe IL-2 receptor structure
In inactive T-cells: dimer with beta subunit and a common gamma chain (ɣc) subunit
In active T-cells: trimeric complex with the same and an alpha subunit
Activated cell receptor complex has a much higher affinity and produced a stronger signal
IL-2 pathway
IL-2 -> JAK 1/3 -> STAT 5 -> Myc ->
IL-2 pathway
IL-2 -> JAK 1/3 -> STAT 5 -> Myc -> other target genes-> cell growth
-> Cdk4/cyclin D -> G phase
