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BCH Final > RTK/GPCR > Flashcards

RTK/GPCR Flashcards

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1
Q

what do receptor tyrosine kinases control

A

the rate of cell proliferation and growth

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2
Q

what do insulin receptors regulate

A

glucose homeostasis

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3
Q

which ligands for RTKs are dimers

A

PDGF - platelet derived
NGF - nerve
VEGF - vascular endothelial

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4
Q

which ligands for RTKS are monomers and what do they cause

A

EGF - epidermal

cause conformational rearrangement of the receptor and dimerization

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5
Q

what is receptor dimerization

A

when two receptor subunits come close to each other

their intracellular domains (tyrosine resideues) cross phosphorylate each other

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6
Q

What does the SH2 domain recognize

A

P-Tyr and 3 AAs on the C terminal side

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7
Q

PTB domain recognizes

A

the N terminal side of P-Tyr

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8
Q

SH3 domain recognizes

A

proline rich sequences

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9
Q

PH domain recognizes

A

lipids: PI bi and triphosphates
=phosphatidylinositol bi and tri’s (PI3, 4P2, & PI3,4,5P3
etc)

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10
Q

RAS is a

A

low molecular weight GTPase

slow GTPase so it’s inefficient

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11
Q

what does GTPase Activating protein do

A

it’s a protein cofactor known as GAP that binds to RAS

turns RAS-GTP into RAS GDP and Pi by increasing efficiency of GTP hydrolysis

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12
Q

what does GDP/GTP exchange factor (GEF) do

A

changes bound GDP to RAS into the active form Ras-GTP so that GTP can be disassociated from RAS

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13
Q

what are the hydrophobic anchors of RAS that attach it to the plasma membrane so that it can participate in signal transaction

A

farnesyl residue

Fatty Acid

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14
Q

what are the domains of GRB2
which is used to bind to active RTK
which domain is used to bind to SOS

A

SH3-SH2-SH3

SH2 binds it to RTK
SH3 binds to SOS

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15
Q

RAS is a significant protein in what

A

cancer with 40% of solid tumors containing a mutation in RAS

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16
Q

what does activation of the MAP kinase pathway control

A

cell proliferation

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17
Q

in the cytosol, ERK controls translation by doing what

A

phosphorylating and inhibiting TSC2

TSC2 is a protein that binds to TSC 1

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18
Q

what do mutations in TSC1 and TSC2 lead to

A

lymphangioleiomyomatosis and tuberous sclerosis complex

-benign tumors in brain, heart, kidneys, skin

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19
Q

TSC2 is a

A

GTPase activating protein for Rheb (Ras homolog enriched in brain)

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20
Q

Rheb/GTP activates ____

A

mTORC1

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21
Q

mTORC1 increases

A

cell growth by stimulating protein synthesis at the level of translation

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22
Q

TSC1/2 complex acts as a ____ and converts ___

A

GAP for Rheb and converts Rheb-GTP to Rheb-GDP inactivating it

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23
Q

how do mutations in TSC1/2 cause tuberous sclerosis complex

A

the TSC1/2 complex is not phosphorylated and inhibited
so the Rheb-GTP is NOT converted to Rheb-GDP (inactive)
so Rheb is in active form Rheb-GTP which activates mTORC1
which increase rate of protein syntheis –> incr size of cell (cell growth) –> cell division rate is same –> tumor formation

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24
Q

what is tuberous sclerosis complex and what’s it caused by

A

autosomal-dominant multisystem disordor
casuses formation of benign tumors all over body
underlying genetic cause: mutation in TSC1 or TSC2 gene
–> overactivation of rapamycin complex (mTORC)

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25
how to treat Tuberous sclerosis complex
mTOR inhibition such as monoclonal antibody Everolimus
26
mTOR is aka ___ which is used in the clinic as ___
rapamycin complex which is used as an antiproliferative drug in treating TSC and certain cancers
27
ways to terminate MAPK pathway | hint: 4 ways
spontaneous hydrolysis of GTP to GDP --> inactivates Ras Ras-GAP (turns Ras-GTP to Ras-GDP) -->inactivates Ras protein phosphatases (dephosphorylate and deactivate every component of the signaling pathway) internalization of the receptor (decr concentration of activated receptor to plasma membrane inhibits the signaling)
28
T/F: | under basal conditions, PI3K type 1A is active
FALSE | it's inactive during basal conditions
29
what are the regulatory and catalytic subunits needed for PI3K path
Regulatory subunit p85 (bound to SH2 domain on receptor to allow p110 to be active) catalytic subunit p110 (bound to Ras-GTP)
30
activation of PI3K increase the concentration of what, where
incr conc of PIP3 in plasma membrane
31
how are PDK1 and AKT recruited to the membrane
via their PH domains
32
how to terminate the PI3K path
protein and lipid (PTEN) phosphatases dephosphorylate PIP3 to make PIP2 --> inhibits AKT path
33
what happens to AKT when under basal conditions
AKT not active | PH domain binds to it's Kinase domain --> inhibits activity
34
what is req'd to get complete activation of AKT
unfolding recruitment to plasma membrane 1 or 2 independent phosphorylation events
35
where does TORC2 phosphorylate AKT
on it's hydrophobic tail
36
what happens when the concentration of PIP3 in the membrane is high
PH domain of AKT binds to PIP3 in plasma membrane enzyme unfolds PH doesn't inhibit kinase anymore PDK1 can phosphorylate the kinae domain while mTORC2 phosphorylates the hydrophobic tail
37
what would happen if there was a mutation of either PTEN or SHIP2
they're used to termination PI3K signaling | so if disfunctional --> hyperactivation of PI3K path --> malignant transformation of cells
38
in the phospholipase C gamma pathway it hydrolyzes ___ which produces ___
hydrolyzes PIP2 --> inositol triphosphate (IP3) & diacylglycerol (DAG)
39
what does IP3 bind to and cause
binds to specific receptors in the ER | releases calcium in the cytosol
40
what does DAG activate
PKC - protein kinase C
41
how does overexpression of ERB2 (aka HER2) lead to breast cancer
incr in basal HER2 signaling incr cell proliferation incr cell growth breast cancer
42
what does a mutation in an N terminal truncation of the Erb or Her receptor result in
dimerization and constant activation of the mutant receptor in the absence of the ligand
43
what are two therapy's for breast cancer
monoclonal antibodies specific inhibitors of the kinase domain
44
what are G-protein coupled receptors
7 transmembrane domain receptors that act as GTP/GDP exchange factors for assc heterotrimeric G proteins
45
after ligand binding, the GPCR acts as a
GTP/GDP exchange factor
46
what happens when GTP is bound to G-alpha
G-alpha dissacosiates from Beta-gamma
47
what is the difference bn isoform alpha-i vs alpha-s
alpha-i inhibits adenylyl cyclases --> reduces cAMP | alpha-s stimulates adenylyl cyclases --> incr cAMP
48
what is different in PI3K type 1B compared to type 1A
type 1B has regulatory subunit type p101 while 1A had p85 | however, they have the same catalytic subunit p110
49
what is the general structure of GCPRS
N terminus on outside of cell C terminus on inside water-soluble molcs bind to extracellular domains hydrophobic molcs bind to transmembrane region
50
which loop does the ligand-occupied GPCR interact w the G protein
via the 3rd intracellular loop usually
51
what happens when a ligand binds to GPCR
it gets rid of GDP and a GTP enters --> dissociation of alpha from beta-gamma
52
T/F | the GTP bound GPCR is the resting state
falso this si the active state | resting is when it is GDP bound
53
how is the beta-gamma SUs attached to the plasma membrane
prenyl group at the C terminus of the gamma SU
54
what anchors the alpha subunit to the mebrane
FA residue at the N terminus
55
GPCR acts as a ____ and facilitates the exchange of ____ at the alpha subunit
GTP/GDP exchange factor and exchanges GDP for GTP at the alpha
56
what is needed for the alpha subunit to hydrolyze the GTP molc
regulator of G protein signaling (RGS) which stimulates the GTPase activity and turns GTP to GDP
57
what are some of the targets of various alpha SUs
``` adenylyl cyclase guanylyl cyclase phosphodiesterase phospholipase ion channels ```
58
what is the target of the beta-gamma complex
PI3K type 1B which has most of the same effects as type 1A
59
cAMP activity is mediated by
PKA
60
cAMP binds to which subunits of PKA
regulatory
61
binding of cAMP to regulatory subunits of PKA causes
their dissociation from the catalytic SU and phosphorylation of the downstream substrates
62
what are the PKA targets and what do they regulate
phosphorylase kinase and glycogen synthase phosphorylation by PKA --> regulates glucose metabolism hormone sensitive lipase phosphorylation --> regulate lipolysis CREB (cAMP response element binding protein) --> regulate transcription
63
PLC-Beta is activated by what subunit
alpha-q
64
activation of PLCB causes
hydrolysis of PIP2 into | DAG and IP3
65
what does Diacyl glycerol do in PLCB
stays on plasma membrane | where it activates PKC
66
what does inositol triphosphate do in PLCB
``` cleaved off the membrane migrates to ER opens the Calcium channels in the ER Calc rushes into cytosol calcium conc increases ```
67
how to terminate PLCB signaling
Calcium-ATPases pump calcium outside the cell or back inside the ER
68
what does calcium bind to
calmodulin
69
what happens upon calmodulin binding to atoms of clacoim
calmodulin changes its conformation and activates the enzyma Calcium/calmodulin-dependent protein kinase
70
what can Calcium/calmodulin-dependent protein kinase phosphorylate
phosphorylase kinase like PKA
71
PKA and PKC can phosphorylate ...
the third intracellular loop and the C terminus of GPCR which impairs its interaction w the G protein
72
ligand bound GPCRs can be phosphorylated on the C terminus by
G protein coupled receptor kinases (GRK) which interact with arrestins
73
what happens when phosphorylated DRKs interact with arrestins
interfere w binding to G proteins | recruit clathrin and promote internalization of GPCRs
74
unlike PKA and PKC, GRK can only phosphorylate ...
agonist occupied receptors i.e. receptors bound to ligands
75
signaling mechanism involved in cholera
cholera toxin ADP-ribosylates alpha-s in the interstinal epithelium and inhibits it's GTPase activity --> rise in cAMP -->disregulates ion channels --> efflux of watetr and electrolytes into the gut -->diarrhea
76
Bacterial ADP-ribosylating exotoxins (bAREs) covalently transfer...
ADP-ribose moiety of NAD+ to target proteins of infected eukaryotes --> yield nicotinamide and free Hydrogen ion
77
pertussis toxin is anoth example of bacterial toxin with ADP-ribosyltransferase activity. what happens when it ADP-ribosylates alpha-i
ADP-ribosylates alpha-i in lung -->blocks intxn w GPCR -->adenylyl cyclase not inhibited -->incr cAMP -->loss of fluids and electrolytes -->incr mucus secretion --> whooping cough
78
what do outer regions of rods habe
membranes with rhodopsin bound to the 11-cis retinal
79
what happens to rods when exposed to light
light coverts it from 1-cis to all-trans retinal --> conformational change in rhodopsin --> GDP to GTP exchange in the alpha SU of transducin (G protein) --> liberated alpha SU --> activates cGMP PDE --> decr in cGMP --> cGMP gated non-selective cation channels cause --> membrane hyperpolarization --> inhibition of synaptic signaling
80
in cone cells,retinal is attached to different opsins so that ...
cis/trans isomerization happens in response to photons with different energy aka light w diff wavelengths: blue, green, red
81
olfactory GPCRsare coupled to
specific g protein: Golf
82
what does Golf activate
adenylyl cyclase --> incr cAMP conc --> opens cAMP gated Na channels --> depolarized -->signal sent to brain
83
which two tastes are mediated by a family of three GPCRs that heterodimerize in diff combos
umami and sweet
84
all taste receptors are coupled to
specific G protein gustducin which activates PLC-beta

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