Lecture 12: Signaling through immune receptors

Question 1

signal transduction is the process of _____ from outside source that activate ________ that are converted into ____ singals/responses

Answer 1

input signals; biochemical pathways; output

Question 2

there are often _____ requirements since some outputs can be dangerous to a cell

Answer 2

threshold

Question 3

the receptor/ligand is the ____

Answer 3

input

Question 4

an example of an input threshold requirement is ________

Answer 4

receptor cross-linking or clustering; F(ab)2 BCR

Question 5

Trimeric _____ released by NK and cytotoxic T cells binds to FAS and ______ it. Death domains cluster so Fas can recruit FADD. _______ recruit procaspase 8.

Answer 5

FasL; trimerizes; DED

Question 6

Receptor signaling can be distributed to _____ or ______

Answer 6

cytoskeleton or nucleus

Question 7

Signals to cytoskeleton impact ________, including ___, _____, and ____

Answer 7

cell morphology: cell shape, size, and mobility

Question 8

Signals to the nucleus impact ______

Answer 8

gene expression: synthesis of new proteins, inducing cell division, proliferation, cell death

Question 9

Protein kinases are enzymes that

Answer 9

catalyze attachment of phosphate

Question 10

Protein phosphatases ______ phosphate group

Answer 10

remove

Question 11

kinases add phosphate to 1 of 3 aa residues:

Answer 11

tyrosine, serine, threonine

Question 12

______ catalyze attachment of a phosphate to a phospholipid

Answer 12

Phospholipid kinases

Question 13

an example of phospholipid kinase

Answer 13

PI3K converts PIP2 -> PIP3

Question 14

_____ carry kinase activity in the cytoplasmic tail of the surface receptor. They have an ____ activity. An example is FLT3 which is involved in hormone differentiation of CD34 cells to produce DC

Answer 14

Receptor tyrosine kinases; intrinsic

Question 15

_____ noncovalently associate with intracellular tyrosine kinases on T and B cells

Answer 15

Nonreceptor kinases

Question 16

propagation of intracellular signaling is mediated by ______

Answer 16

multiprotein signaling complexes

Question 17

multiprotein signaling complexes can be common to several pathways and have distinct binding domains such as ___ and ___, which are generally found in _____ molecules

Answer 17

SH2/SH3; adaptor

Question 18

SH is part of ____ homology (a nonreceptor tyrosine kinase)

Answer 18

Src

Question 19

______ proteins (ex: LAT) are like power strip - many things can bind

Answer 19

scaffolding

Question 20

______ proteins (ex: Grb2) link one protein to another (like a wall block)

Answer 20

Adaptor

Question 21

_____ binds to SLP76. It makes a docking site complex for _____ during TCR signaling. It allows this molecule to be activated by phosphorylation by Itk

Answer 21

LAT; PLC-gamma

Question 22

adaptor protein ____ recruits Sos via its ____ domain to an activated receptor that is tyrosine phosphorylated via its ___ domain

Answer 22

Grb2; SH3; SH2

Question 23

Sos does activity on Ras as ____

Answer 23

GEF (guanine-nucleotide exchange factor)

Question 24

SH2 binds in ___ format

Answer 24

pYXXZ (three aa away from phosphorylated tyrosine)

Question 25

SH3 binds in ___ format

Answer 25

XPPXP (proline in 2nd and 5th position)

Question 26

____ is a small G protein associated with pancreatic cancers

Answer 26

Ras

Question 27

GTPases act as ______, triggered by GEF

Answer 27

on/off switch

Question 28

Ras bound to ____ is inactive and is active when bound to _____.

Answer 28

GDP; GTP

Question 29

___ helps to open up Ras bound to GDP so that it can be exchanged for GTP

Answer 29

GEF

Question 30

_____ are recruited to the site of receptor activation

Answer 30

GEFs

Question 31

The active receptor molecule is

Answer 31

GTP:Ras

Question 32

activity of small G proteins will lead to shutdown/feedback conversion of ___ to ____. Alterations in this regulatory process lead to cancer.

Answer 32

GTP to GDP

Question 33

_____ is the process of a kinase cascade

Answer 33

Amplification

Question 34

_____ is example of kinase cascade (adding a kinase to a kinase). The higher the number = further upstream from the outcome

Answer 34

MAP (mitogen-activated protein)

Question 35

Ras/MAP kinase

Answer 35

TCR signaling produces DAG, which recruits RasGRP where it activates Ras at the membrane. Ras binds to Sos - enhances Sos activity and amplifies Ras activation. Ras activates Raf (MAP3K), which phosphorylates Mek (MAP2K), which phosphorylates Erk (MAPK). Erk enters nucleus and activates TF like Elk-1

Question 36

second messengers are small molecule biochemical _____ that diffuse through the cell

Answer 36

mediators

Question 37

calcium ion influx from the ER to the cytosol is an example of ______. Ca2+ modifies _____ to act on effector protein that activates _______ which dephosphorylates and activates NFAT and transcription of IL2

Answer 37

second messenger; calmodulin; calcineurin

Question 38

Regulation: kinase activity is often modulated by _____ activity

Answer 38

phosphatase

Question 39

Signaling can be regulated by ______ and tagged for proteasomes

Answer 39

ubiquination

Question 40

____ can turn on the proteasome that targets for MHC I

Answer 40

IFN-gamma

Question 41

receptors and ligands can be directly ______ by antibodies, soluble receptors, and non-activating ligands

Answer 41

inhibited

Question 42

what is signal 1?

Answer 42

antigen specific interaction between MHC and TCR (this is the antigen you need to interact with)

Question 43

what is signal 2?

Answer 43

other info from APC regarding how serious the infection is, guiding the response

Question 44

CD3 is made up of

Answer 44

delta, epsilon or gamma, epsilon

Question 45

there are 2 _____ (homodimers) in cytoplasm underneath TCR

Answer 45

zeta chains

Question 46

ITAMs (immunereceptor tyrosine based activation motifs) have 2 ___ domains and are present on cytoplasmic tail of ___

Answer 46

SH2; CD3 (4 total) and zeta (3 on each)

Question 47

Phosphorylated ITAMs recruit _____ with tandem SH2 domains

Answer 47

ZAP70

Question 48

______ is an example of ITIM on NK cell that stops NK cell from killing a self cell (recognizes MHC)

Answer 48

NKG2A

Question 49

_____ is an example of ITIM that stops T cells from killing. Blocking the receptor would allow T cells to keep killing (cancer drug)

Answer 49

PD-1

Question 50

ITIMs are _____ and recruit inhibitory phosphatases that ______ signaling pathways

Answer 50

phosphorylated; deactivate

Question 51

____ helps TCR if its engaged to MHC II and enhances the signal to TCR

Answer 51

CD4

Question 52

___ (on tail of CD4) adds phosphate to ITAMs (especially __ chains)

Answer 52

Lck; zeta

Question 53

phosphorylation of TCR ITAMs by Lck, recruits _____ through tandem _____ domain

Answer 53

ZAP70; SH2

Question 54

____ phosphorylates ZAP70

Answer 54

Lck

Question 55

Lck on CD4/8 is _______ when phsophorylated on terminal tyrosine that binds the ___ domain and linker region binds ___ domain

Answer 55

inactive; SH2; SH3

Question 56

_____ removes phosphate from Lck to activate it. TCR co-localize and polarize, pushing away ___. Physical contact between ____ and TCR removes phosphate group.

Answer 56

CD45

Question 57

Lck is active when _____ is removed and _____ domain releases linker region

Answer 57

phosphate; SH3

Question 58

Lck and ___ are both invovled in phosphorylated ITAMs and recruiting ZAP70

Answer 58

Fyn

Question 59

ZAP70 is an early factor in 4 downstream signaling pathways. It begins by recruiting ____ and ____. ____ activation leads to metabolic activity _____ activation leads to transcription of cytokines ___ activation leads to cytoskeletal (actin) reorganization ____ activation leads to adhesiveness clustering

Answer 59

LAT and SLP76; Akt Plc-gamma Vav ADAP

Question 60

_______ phosphorylates and recruits scaffolding proteins LAT and SLP-76. Adaptor protein ______ holds LAT and SLP-76 together to create docking site.

Answer 60

ZAP70; Gads

Question 61

____ costimulation (signal 2 from APC) recruits and activates PLC-gamma

Answer 61

CD28

Question 62

DC have costimulatory molecules ____ and ___. Both signals binding to CD28 induce phosphorylation and activate _____ kinase to produce PIP3.

Answer 62

CD80 and CD86 (or B7.1 and B7.2); PI3

Question 63

PIP3 role

Answer 63

- recruits PLC-gamma - Recruits Itk to membrane

Question 64

____ is recruited by PIP3 and phosphorylates PLC-gamma

Answer 64

Itk

Question 65

How do signal 1 and 2 work together?

Answer 65

signal 1: TCR leads to ZAP-70 activation, resulting in LAT/SLP76 complex, where PLC-gamma can dock signal 2: CD28 costimulation activates PI3 kinase which converts PIP2 to PIP3. PIP3 recuits Itk and PLC-gamma, PLC-gamma can dock and be activated by Itk

Question 66

PLC-gamma function

Answer 66

cleave PIP2

Question 67

PIP2 is cleaved into

Answer 67

IP3 and DAG

Question 68

IP3 function

Answer 68

- diffuses from membrane and allows for calcium influx from ER to cytoplasm and from outside cell - Ca2+ leads to activation NFAT

Question 69

DAG function

Answer 69

- PKC activator (activates NF-kappaB) - recruits Ras-GRP (GEF) to activate RAS, MAP kinase cascade, and TF AP-1 (IL-2 cytokines)

Question 70

in the lab, _____ is a DAG mimic and ______ is IP3 mimic

Answer 70

PMA; ionomycin