B3.059 - Signal Tranduction

Question 1

What do kinases do

Answer 1

Add phosphates

Question 2

What do phosphatases do

Answer 2

Take a phosphate from something

Question 3

Whats an example of a receptor that exhibits kinase activity

Answer 3

Growth factor receptors

Question 4

What type of receptors associate with kinases all the time (not an intrinsic part of the receptor)

Answer 4

Cytokines receptors

Question 5

What type of receptor associates with receptors after ligand binding

Answer 5

Antigen receptors (B and T cell signaling)

Question 6

What are JAKs

Answer 6

Two near identical phosphate transferring domains that have kinase activity and negatively regulate the kinase activity

Question 7

What type of kinase is JAK

Answer 7

Tyrosine kinase

Question 8

JAKs associate to what type of membrane

Answer 8

Proline rich region of proximal receptor

Question 9

What are JAKs two domains

Answer 9

Box 1 and 2

Question 10

What are STATS

Answer 10

Signal transducers and activators of transcription

Question 11

How are STATS phosphorylated

Answer 11

By JAK, RTK, c-src

Question 12

What do STATs bind to

Answer 12

GAS

Question 13

What provides the nuclear localization signal in STATs

Answer 13

Coiled coil domain

Question 14

What domain for JAK is critical for its ability to associate once its been phosphorylated

Answer 14

SH2 domain

Question 15

What cytokines utilize the shared gamma common chain and what JAKs do they use

Answer 15

IL2R, 4R, 7R, 9R, 15R, 21R

JAK1 and 3

Question 16

General model of signal transduction mediated by most class I and class II cytokines receptors

Answer 16

1. Binding of cytokines causes dimerization of receptors and activation of JAK kinases
2. Activated JAK kinases phosphorylate receptor sites and create docking sites for STAT molecules
3. The phosphorylated STATs dimerize and translocate to the nucleus where they activate specific genes

Question 17

What are type 1 interferons

Answer 17

IFN alpha and beta
JAK 1, TYK2
STAT1 and 2

Question 18

Type 2 interferon

Answer 18

IFN gamma
JAK1 and 2
STAT1-STAT1

Question 19

IL2 has a high has what type of receptor

Answer 19

High affinity

Question 20

What JAKs does IL2 use and what STATs

Answer 20

JAK1, 3

STAT5a, STAT5b

Question 21

IL2 receptors subfamily utilizes what subunit

Answer 21

Common gamma subunit aka CD132

Question 22

Patients missing the gamma common chain have what

Answer 22

Severe X linked SCID

Question 23

Patients with X linked SCID don’t produce what cytokines and what effect does that have

Answer 23

IL7 (don’t produce T cells)
and IL15 (don’t produce NK cells)

Question 24

What do X linked SCID patients have normal levels and what does that indicate

Answer 24

B cells, indicating a common gamma chain isn’t required for B cell production

Question 25

How is specificity achieved

Answer 25

Unique ligand binding receptors

Question 26

What phosphatases/molecules prevent phosphorylation

Answer 26

``` SHP1, SHP2 (SH2 domain) SHIP (SH2 domain) CD45 SOCS PIAS ```

Question 27

What do SOCS and PIAS do and how does that differ from SHIPS/SHPs

Answer 27

They prevent further phosphorylation, while SHIPs/SHPs can dephosphorylate

Question 28

What is a kinase inhibitory region and what has it

Answer 28

SOCS1 and SOCS3 | It inhibits JAK kinase activity, prevents phosphorylation

Question 29

Whats a SOCS box

Answer 29

Helps target the entire cytokines receptor complex for ubiquitin mediated proteosomal degradation

Question 30

How does the KIR inhibit JAK kinase activity

Answer 30

Binds activation loop of JAK catalytic domain and functions as a pseudosubstrate

Question 31

What is high SOC3 associated with

Answer 31

M1 macrophage polarization

Question 32

What is a high SOCS1 to SOCS3 ratio associated with

Answer 32

M2 macrophage polarization

Question 33

What does ruxolitinib do

Answer 33

Inhibits JAK1 and JAK2 | Reduces spleen size (size of extramedullary hematopoeisis)

Question 34

What disease does ruxolitinib treat

Answer 34

Myelofibrosis

Question 35

What does Tofacitinib do

Answer 35

Inhibits JAK3 | Interferes with IL2 and IL4 signaling

Question 36

What is tofacitinib used for

Answer 36

Rheumatoid arthritis

Question 37

Where are TLRs found

Answer 37

Macrophages, dendritic cells, detect a wide range of ligands

Question 38

What does TL4 sense

Answer 38

LPS

Question 39

What 2 pathways does TLR4 use

Answer 39

Myd88 dependent | Myd88 independent

Question 40

Which TLR4 pathways is the fast pathway

Answer 40

MyD88 dependent

Question 41

Which TLR4 pathway is the slow pathway

Answer 41

MyD88 independent

Question 42

What does the fast pathway for TLR4 stimulate the creation of

Answer 42

Pro inflammatory cytokines

Question 43

What does the slow TLR4 pathway stimulate the transcription of

Answer 43

Type 1 interferons

Question 44

How does NFkB mediated gene transcription work

Answer 44

Requires phosphorylation of IkB by IKK complex to liberate NFkB translocate to the nucleus to regulate gene expression

Question 45

What do CD4 T cells increase production of

Answer 45

Cytokines producers

Question 46

What do CD8 T cells increase production of

Answer 46

Cytotoxic mediators

Question 47

What is always associated with CD4/8 receptors

Answer 47

Lck

Question 48

What is CD45

Answer 48

A phosphatase

Question 49

What does Lck do

Answer 49

Phosphorylate ITAMs in CD3 chains recruiting ZAP 70 to receptor complex, which phosphorylates many linker/adaptor proteins of the distal T cell activation pathway

Question 50

What are some important things that Zap 70 phosphorylate seems

Answer 50

LAT and Slp76 providing a scaffold for downstream signaling events

Question 51

What does the PLC gamma mediated pathway increase the production of

Answer 51

Calcium and IL2 production

Question 52

What does IL2 do

Answer 52

Promotes T cell growth and survival, differentiation into effector cells and memory cells and is required for T reg cells

Question 53

How does PLC gamma induced increase of calcium cause induction of IL2

Answer 53

It generates PIP3 and DAG which activate PKC required for NFkB activation

Question 54

What doe IP3 do

Answer 54

Opens calcium channels to allow Ca2 release from ER into cytosol, leading to aggregation of STIM 1 allowing calcium from extra cellular environment to come in and replenish stores

Question 55

Describe the role of NFAT in IL2 production

Answer 55

NFAT is dephosphorylated by calcium entry which activates it, allowing it to enter the nucleus and activate gene transcription

Question 56

What does cyclosporine/tacrolimus do

Answer 56

Prevents dephosphorylation of NFAT leading to suppression of IL2 transcription used for transplant patients

Question 57

How are cyclosporine and Tacrolimus different in their mechanism

Answer 57

Tacrolimus binds FK506 blocking CaN inhibiting NFATc activation/movement to nucleus so no IL2 is produced Cyclosporine does something similar except it binds Cpn and blocks CaN which would normally activates NFATc through dephosphorylation

Question 58

What are ITIMs

Answer 58

Immunorecptor tyrosine based inhibitory motifs (PD-1, BTLA)

Question 59

What does CTLA-4 do

Answer 59

Outcompetes CD28 on T cells so provides inhibitory signal

Question 60

What does ipilimumab do

Answer 60

Targets CTLA4

Question 61

What does pembrolizumab (Keytruda) do

Answer 61

Targets PD-1

Question 62

What do T reg cells

Answer 62

Maintain self tolerance | Suppress self reactive lymphocytes

Question 63

Where do T Regs develop

Answer 63

Thymus

Question 64

What is the outcome of B cell activation

Answer 64

``` Production of memory cells Ig class switching Terminal differentiation into Ab secreting plasma cells ```

Question 65

What are important in T cell dependent B cell activation

Answer 65

Cytokines produced by CD4 T cells