biol454 receptor signaling

protein phosphorylation is a common mode of … in cells

regulation

.. messengers are key components of signaling

second

(t/f) in response to a signal, a cell may regulate activities in the initial cytosolic phase or nuclear phase

true

how does phosphatase stop signaling?

removal of phosphate groups

what degradation of signaling component can stop or activate signaling pathway?

ubiquitin-degradation

this domain recognizes p-Tyr peptides

SH2

this domain mediates protein-protein interactions by binding to proline rich regions

SH3

this domain binds to p-lipid PIP3 and PIP2 or inositol

PH (pleckstrin homology)

what links multiple kinases/enzymes together to promote assembly of larger signaling ocmplexes?

adaptor proteins

extracellular domains of surface proteins do what to initiate signaling?

recognize soluble secreted ligands or molecules on neighboring cell surface

how do non-receptor tyrosine kinases work?

• separate intracellular tyrosine kinase interacts with receptor to phosphorylate the receptor or other interacting proteins

what differentiates tyrosine kinases from non-receptor tyrosine kinases?

membrane receptor has no intrinsic catalytic activity in non-receptor

antigen receptors (BCR, TCR), cytokine receptors, and integrin receptors use what type of immune receptor signaling?

non-receptor tyrosine kinases

non-receptor TK (1)

binding of the ligand initiates Tyrosine kinase doing what?

phosphorylation of Y a.a residue

non-receptor TK (2)

after Y is phosphorylated, what occurs?

• recognized by second protein

• initiates next step in protein cascade

what is associated with the cytoplasmic tail of the cytokine receptor?

JAKs

when the cytokine receptor is bound to a cytokine, what conformation change occurs?

dimerization

in the JAK-STAT pathway…

what recognizes the phosphorylated receptor tail?

STATs

in the JAK-STAT pathway…

what phosphorylates the STAT?

JAKs

in the JAK-STAT pathway…

the pSTAT forms a dimer and does what?

dissociates from the receptor tail

in the JAK-STAT pathway…

what are active transcription factors that induce gene expression? where do they translocate to?

pSTAT, nucleus

(t/f) common gamma chain (yc) is used as a receptor subunit for certain cytokine receptors

true

severe combined immunodeficiency (SCID) is due to mutations in the common gamma gene, which leads to

defects in IL-signaling

how are BCR and TCR signaling similar to antigen receptor signaling?

• receptor clustering

• Src family are initial non-receptor TKs

• activate through ITAM

what is fine tuned by

• progressive ITAM use

• co-receptor modulated signals

• inhibitory receptors

antigen receptor signaling

what do these signals induce?

weak → ?

strong → ?

weak → positive selection

strong → negative selection (cell death)

the interaction of TCR with Ag:MHC is associated with what complex?

CD3

which complex consists of:

• heterodimers of gamma or delta chains

• zeta chains

CD3

CD3 signaling molecules have ITAM/ITIM motifs

ITAM

what receptors are crucial in the first step of TCR complex ITAM phosphorylation

CD4 and CD8 co-receptors

when does CD3-zeta open up their ITAMs?

when TCR binds to pMHC

when CD3 zeta chains are brought together by pMHC binding, it causes Src kinases to…

be able to phosphorylate ITAMS

how does TCR pMHC binding change the conformation of CD3 zeta chains?

• CD3 zeta opens up their itams

• zeta chains close together

• Src kinases phosphorylate ITAMs

clustering inside lipid rafts is due to what binding to TCR?

MHC:Ag complex

when MHC:Ag binds to TCR, what type of co-receptors cluster in lipid raft?

CD4 or CD8 co-receptors

Which Src family kinase is associated with the cytoplasmic domain of coreceptors CD4 or CD8

LCK

What is the significance of supramolecular activation cluster? (SMAC)

region of contact between T cell and APC

TCR complex recognizes MHC:peptide in the middle of what?

synapse or c-SMAC

(t/f) p-SMAC has integrins on the outside

true

why is clustering important with low amounts of pMHCs?

better trigger multiple TCRs

(t/f) in the resting T cell, ITAMs are phosphorylated

false, they are not phosphorylated

when a TCR complex activates, what phosphorylates Tyr on CD3 complex ITAMs?

LCK

P-Tyr on CD3 serves as a docking site for

ZAP-70

what kinase is this?

• Syk family

• SH2 domains

• bind to p-Y on ITAM

ZAP-70

what:

• binds phosphotyrosines

• phosphorylates adaptor proteins like LAT

ZAP-70

when ZAP-70 phosphorylates major adaptor protein LAT, what occurs?

multiple signal molecules coming together

what major adaptor protein is responsible for starting cascades that activate…

• NFAT

• AP-1

• NfKb

LAT

when PLCy1 is recruited, it is added to what two domains?

• pLAT (SH2)

• membrane PIP-3 (PH)

PLCy1 hydrolyzes membrane PIP2 to make… (2)

free IP3 and membrane-DAG (diacylglycerol)

a receptor on the ER recognizes cytosolic IP3 and does what?

depletes ER Ca++ levels

how does PLCy1 initiate Ca++ through PIP2 hydrolysis?

1. PLCy1 recruited and binds to pLAT and membrane PIP3

2. hydrolyzes PIP2

3. frees IP3 and membrane-DAG

4. receptor recognizes cytosolic IP3

what happens when STIM in the ER membrane senses low Ca++ levels in the lumen?

it opens up CRAC on the plasma membrane

(t/f) Ca++ flux happens within 15 minutes of TCR:pMHC binding

true

phosphatase Calcineurin is activated by what Ca++-dependent protein?

Calmodulin

NFAT goes into the nucleus when dephosphorylated by?

calcineurin

PLCy1 hydrolysis of PIP2 frees what 2 molecules?

IP3 and membrane DAG

how are membrane DAG and NF-kB associated?

• membrane DAG recognized by and activates PKC0

• PKC0 activates NF-kB

(t/f) LAT is only necessary for:

• PLCy1 → NFAT

• Grb2-SOS → AP-1

false, missing PLCy1 → NFkB

• LAT bound Grb2-SOS exchanges GDP

• puts in a GTP in RAS → RAS-GTP

what pathway is activated?

MAP kinase pathway

how is membrane DAG associated in activation of the MAP kinase pathway?

• mDAG bound by RasGRP1

• exchanges RAS-GDP to RAS-GTP

what are the two ways to activate RAS-GTP?

• LAT- GrbSOS

• DAG - RasGRP

• PI3 kinase phosphorylates PIP2 → PIP3

• PIP3 is recognized by ? and phosphorylates AKT

PDK1

what kinase inactivates pro-apoptosis factors leading to proliferation?

AKT