Cytokine Receptors: Signalling and Function

Question 1

Cytokine

Answer 1

Any class of immunoregulatory proteins (such as interleukin or interferon) that are secreted by cells, especially of the immune system

Question 2

What do cytokines do?

Answer 2

Control the function of other cells

Question 3

What physiological processes do cytokines regulate

Answer 3

Hematopoiesis (formation of blood cell components)
Immunity (function of WBCs)
Inflammation

Question 4

What are the four major categories of cytokines and their functions

Answer 4

Interferons: anti-viral activity
Tumour necrosis factors (TNF): inflammatory response
Chemokines: control and direct cell migration
Interleukins: various

Question 5

What family of receptors do cytokines (mostly) signal through (receptor superfamily not cytokine receptor type)

Answer 5

kinase-linked, the receptor is non-catalytic, must activate intracellular kinases

Question 6

What type of cytokine receptors do most cytokines bind

Answer 6

Type I/II

Question 7

What type of cytokine receptors regulate JAK/STAT pathways

Answer 7

Type I/II

Question 8

What is a JAK

Answer 8

Janus kinase, a tyrosine kinase that is pre-associated constitutively with the receptors of cytokine receptors

Question 9

What happens when ligand binding occurs on an alpha-chain cytokine receptor subunit

Answer 9

Beta chain and associated JAKs are bought closer and phosphorylate each other, activating tyrosine residues on the intracellular tail

Question 10

What is the cytokine homology region (CHR)

Answer 10

conserved “Bent elbow structure” of cytokine receptor ligand binding region, ligand binds the outside of the elbow

Question 11

How is specificity achieved in cytokine receptors

Answer 11

The 3D structures associated with the cytokine homology domain

Question 12

What is in the JAK family

Answer 12

JAK1, JAK2, JAK3, Tyk2

Question 13

Explain the domains of a JAK

Answer 13

FERM containing the SH2 domain, psi kinase domain containing nucleotide binding site, kinase domain containing ATP binding site

Question 14

What do phosphorylated tyrosine residues activate in class I/II kinase-linked cytokine receptors

Answer 14

STAT dimers, once phosphorylated STAT dimers assume an active dimer conformation

Question 15

What do STAT dimers do when activated

Answer 15

the nucleus where it binds specific DNA specific

Question 16

Which domain of cytokine receptor subunits serves as a docking site for STAT transcription factors

Answer 16

SH2 domain of receptor subunit

Question 17

Explain SH2 domain sites, function and specificity

Answer 17

two binding sites: one for amino acid side chains which gives specificity to the interaction and one for binding phosphorylated tyrosine (phosphotyrosine/pY)

Question 18

on what proteins are SH2 domains commonly found

Answer 18

adaptor proteins that aid in signal transduction of kinase linked receptors

Question 19

How do STAT dimers form

Answer 19

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

Question 20

What are the signal transducers and activators of transcription family members

Answer 20

STAT1
STAT2
STAT3
STAT4
STAT5a/b
STAT6

Question 21

what type of feedback loop do cytokine, JAK, STAT pathways mostly activate

Answer 21

negative

Question 22

What mechanisms do suppressor of cytokine signalling (SOCS) proteins use to negatively regulate cytokine receptor signalling

Answer 22

• 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

Question 23

why do SOCS need fine control

Answer 23

too little inhibition of cytokine signalling means hyperactivity of pathways
too much inhibition of cytokine signalling means autoimmune disease - no immune response

Question 24

Where is Interleukin-2 (IL-2) produced and what is its function

Answer 24

Produced by antigen-activated cells and it acts as a major growth factor/mitogen for antigen-activated T cells

Question 25

In what manner does IL-2 function (_____crine)

Answer 25

Autocrine and paracrine

Question 26

Describe IL-2 receptor structure

Answer 26

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

Question 27

IL-2 pathway

Answer 27

IL-2 -> JAK 1/3 -> STAT 5 -> Myc ->

Question 28

IL-2 pathway

Answer 28

IL-2 -> JAK 1/3 -> STAT 5 -> Myc -> other target genes-> cell growth
-> Cdk4/cyclin D -> G phase