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IBI Test 4 > B3.059 - Signal Tranduction > Flashcards

B3.059 - Signal Tranduction Flashcards

1
Q

What do kinases do

A

Add phosphates

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2
Q

What do phosphatases do

A

Take a phosphate from something

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3
Q

Whats an example of a receptor that exhibits kinase activity

A

Growth factor receptors

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4
Q

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

A

Cytokines receptors

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5
Q

What type of receptor associates with receptors after ligand binding

A

Antigen receptors (B and T cell signaling)

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6
Q

What are JAKs

A

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

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7
Q

What type of kinase is JAK

A

Tyrosine kinase

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8
Q

JAKs associate to what type of membrane

A

Proline rich region of proximal receptor

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9
Q

What are JAKs two domains

A

Box 1 and 2

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10
Q

What are STATS

A

Signal transducers and activators of transcription

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11
Q

How are STATS phosphorylated

A

By JAK, RTK, c-src

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12
Q

What do STATs bind to

A

GAS

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13
Q

What provides the nuclear localization signal in STATs

A

Coiled coil domain

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14
Q

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

A

SH2 domain

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15
Q

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

A

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

JAK1 and 3

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16
Q

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

A
  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
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17
Q

What are type 1 interferons

A

IFN alpha and beta
JAK 1, TYK2
STAT1 and 2

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18
Q

Type 2 interferon

A

IFN gamma
JAK1 and 2
STAT1-STAT1

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19
Q

IL2 has a high has what type of receptor

A

High affinity

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20
Q

What JAKs does IL2 use and what STATs

A

JAK1, 3

STAT5a, STAT5b

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21
Q

IL2 receptors subfamily utilizes what subunit

A

Common gamma subunit aka CD132

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22
Q

Patients missing the gamma common chain have what

A

Severe X linked SCID

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23
Q

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

A 
IL7 (don’t produce T cells)
and IL15 (don’t produce NK cells)
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24
Q

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

A

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

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25
Q

How is specificity achieved

A

Unique ligand binding receptors

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26
Q

What phosphatases/molecules prevent phosphorylation

A 
SHP1, SHP2 (SH2 domain)
SHIP (SH2 domain)
CD45
SOCS
PIAS
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27
Q

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

A

They prevent further phosphorylation, while SHIPs/SHPs can dephosphorylate

28
Q

What is a kinase inhibitory region and what has it

A

SOCS1 and SOCS3

It inhibits JAK kinase activity, prevents phosphorylation

29
Q

Whats a SOCS box

A

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

30
Q

How does the KIR inhibit JAK kinase activity

A

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

31
Q

What is high SOC3 associated with

A

M1 macrophage polarization

32
Q

What is a high SOCS1 to SOCS3 ratio associated with

A

M2 macrophage polarization

33
Q

What does ruxolitinib do

A

Inhibits JAK1 and JAK2

Reduces spleen size (size of extramedullary hematopoeisis)

34
Q

What disease does ruxolitinib treat

A

Myelofibrosis

35
Q

What does Tofacitinib do

A

Inhibits JAK3

Interferes with IL2 and IL4 signaling

36
Q

What is tofacitinib used for

A

Rheumatoid arthritis

37
Q

Where are TLRs found

A

Macrophages, dendritic cells, detect a wide range of ligands

38
Q

What does TL4 sense

A

LPS

39
Q

What 2 pathways does TLR4 use

A

Myd88 dependent

Myd88 independent

40
Q

Which TLR4 pathways is the fast pathway

A

MyD88 dependent

41
Q

Which TLR4 pathway is the slow pathway

A

MyD88 independent

42
Q

What does the fast pathway for TLR4 stimulate the creation of

A

Pro inflammatory cytokines

43
Q

What does the slow TLR4 pathway stimulate the transcription of

A

Type 1 interferons

44
Q

How does NFkB mediated gene transcription work

A

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

45
Q

What do CD4 T cells increase production of

A

Cytokines producers

46
Q

What do CD8 T cells increase production of

A

Cytotoxic mediators

47
Q

What is always associated with CD4/8 receptors

A

Lck

48
Q

What is CD45

A

A phosphatase

49
Q

What does Lck do

A

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

50
Q

What are some important things that Zap 70 phosphorylate seems

A

LAT and Slp76 providing a scaffold for downstream signaling events

51
Q

What does the PLC gamma mediated pathway increase the production of

A

Calcium and IL2 production

52
Q

What does IL2 do

A

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

53
Q

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

A

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

54
Q

What doe IP3 do

A

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

55
Q

Describe the role of NFAT in IL2 production

A

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

56
Q

What does cyclosporine/tacrolimus do

A

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

57
Q

How are cyclosporine and Tacrolimus different in their mechanism

A

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

58
Q

What are ITIMs

A

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

59
Q

What does CTLA-4 do

A

Outcompetes CD28 on T cells so provides inhibitory signal

60
Q

What does ipilimumab do

A

Targets CTLA4

61
Q

What does pembrolizumab (Keytruda) do

A

Targets PD-1

62
Q

What do T reg cells

A

Maintain self tolerance

Suppress self reactive lymphocytes

63
Q

Where do T Regs develop

A

Thymus

64
Q

What is the outcome of B cell activation

A 
Production of memory cells
Ig class switching 
Terminal differentiation into Ab secreting plasma cells
65
Q

What are important in T cell dependent B cell activation

A

Cytokines produced by CD4 T cells

IBI Test 4 (12 decks)

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