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BCH Final > RTK/GPCR > Flashcards

RTK/GPCR Flashcards

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
Q

how to treat Tuberous sclerosis complex

A

mTOR inhibition such as monoclonal antibody Everolimus

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26
Q

mTOR is aka ___ which is used in the clinic as ___

A

rapamycin complex which is used as an antiproliferative drug in treating TSC and certain cancers

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27
Q

ways to terminate MAPK pathway

hint: 4 ways

A

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)

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28
Q

T/F:

under basal conditions, PI3K type 1A is active

A

FALSE

it’s inactive during basal conditions

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29
Q

what are the regulatory and catalytic subunits needed for PI3K path

A

Regulatory subunit p85 (bound to SH2 domain on receptor to allow p110 to be active)

catalytic subunit p110 (bound to Ras-GTP)

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30
Q

activation of PI3K increase the concentration of what, where

A

incr conc of PIP3 in plasma membrane

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31
Q

how are PDK1 and AKT recruited to the membrane

A

via their PH domains

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32
Q

how to terminate the PI3K path

A

protein and lipid (PTEN) phosphatases dephosphorylate PIP3 to make PIP2 –> inhibits AKT path

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33
Q

what happens to AKT when under basal conditions

A

AKT not active

PH domain binds to it’s Kinase domain –> inhibits activity

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34
Q

what is req’d to get complete activation of AKT

A

unfolding
recruitment to plasma membrane
1 or 2 independent phosphorylation events

35
Q

where does TORC2 phosphorylate AKT

A

on it’s hydrophobic tail

36
Q

what happens when the concentration of PIP3 in the membrane is high

A

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
Q

what would happen if there was a mutation of either PTEN or SHIP2

A

they’re used to termination PI3K signaling

so if disfunctional –> hyperactivation of PI3K path –> malignant transformation of cells

38
Q

in the phospholipase C gamma pathway it hydrolyzes ___ which produces ___

A

hydrolyzes PIP2 –> inositol triphosphate (IP3) & diacylglycerol (DAG)

39
Q

what does IP3 bind to and cause

A

binds to specific receptors in the ER

releases calcium in the cytosol

40
Q

what does DAG activate

A

PKC - protein kinase C

41
Q

how does overexpression of ERB2 (aka HER2) lead to breast cancer

A

incr in basal HER2 signaling
incr cell proliferation
incr cell growth
breast cancer

42
Q

what does a mutation in an N terminal truncation of the Erb or Her receptor result in

A

dimerization and constant activation of the mutant receptor in the absence of the ligand

43
Q

what are two therapy’s for breast cancer

A

monoclonal antibodies

specific inhibitors of the kinase domain

44
Q

what are G-protein coupled receptors

A

7 transmembrane domain receptors that act as GTP/GDP exchange factors for assc heterotrimeric G proteins

45
Q

after ligand binding, the GPCR acts as a

A

GTP/GDP exchange factor

46
Q

what happens when GTP is bound to G-alpha

A

G-alpha dissacosiates from Beta-gamma

47
Q

what is the difference bn isoform alpha-i vs alpha-s

A

alpha-i inhibits adenylyl cyclases –> reduces cAMP

alpha-s stimulates adenylyl cyclases –> incr cAMP

48
Q

what is different in PI3K type 1B compared to type 1A

A

type 1B has regulatory subunit type p101 while 1A had p85

however, they have the same catalytic subunit p110

49
Q

what is the general structure of GCPRS

A

N terminus on outside of cell
C terminus on inside
water-soluble molcs bind to extracellular domains
hydrophobic molcs bind to transmembrane region

50
Q

which loop does the ligand-occupied GPCR interact w the G protein

A

via the 3rd intracellular loop usually

51
Q

what happens when a ligand binds to GPCR

A

it gets rid of GDP and a GTP enters –> dissociation of alpha from beta-gamma

52
Q

T/F

the GTP bound GPCR is the resting state

A

falso this si the active state

resting is when it is GDP bound

53
Q

how is the beta-gamma SUs attached to the plasma membrane

A

prenyl group at the C terminus of the gamma SU

54
Q

what anchors the alpha subunit to the mebrane

A

FA residue at the N terminus

55
Q

GPCR acts as a ____ and facilitates the exchange of ____ at the alpha subunit

A

GTP/GDP exchange factor and exchanges GDP for GTP at the alpha

56
Q

what is needed for the alpha subunit to hydrolyze the GTP molc

A

regulator of G protein signaling (RGS) which stimulates the GTPase activity and turns GTP to GDP

57
Q

what are some of the targets of various alpha SUs

A 
adenylyl cyclase
guanylyl cyclase
phosphodiesterase
phospholipase
ion channels
58
Q

what is the target of the beta-gamma complex

A

PI3K type 1B which has most of the same effects as type 1A

59
Q

cAMP activity is mediated by

A

PKA

60
Q

cAMP binds to which subunits of PKA

A

regulatory

61
Q

binding of cAMP to regulatory subunits of PKA causes

A

their dissociation from the catalytic SU and phosphorylation of the downstream substrates

62
Q

what are the PKA targets and what do they regulate

A

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
Q

PLC-Beta is activated by what subunit

A

alpha-q

64
Q

activation of PLCB causes

A

hydrolysis of PIP2 into

DAG and IP3

65
Q

what does Diacyl glycerol do in PLCB

A

stays on plasma membrane

where it activates PKC

66
Q

what does inositol triphosphate do in PLCB

A 
cleaved off the membrane 
migrates to ER
opens the Calcium channels in the ER 
Calc rushes into cytosol 
calcium conc increases
67
Q

how to terminate PLCB signaling

A

Calcium-ATPases pump calcium outside the cell or back inside the ER

68
Q

what does calcium bind to

A

calmodulin

69
Q

what happens upon calmodulin binding to atoms of clacoim

A

calmodulin changes its conformation and activates the enzyma Calcium/calmodulin-dependent protein kinase

70
Q

what can Calcium/calmodulin-dependent protein kinase phosphorylate

A

phosphorylase kinase like PKA

71
Q

PKA and PKC can phosphorylate …

A

the third intracellular loop and the C terminus of GPCR which impairs its interaction w the G protein

72
Q

ligand bound GPCRs can be phosphorylated on the C terminus by

A

G protein coupled receptor kinases (GRK) which interact with arrestins

73
Q

what happens when phosphorylated DRKs interact with arrestins

A

interfere w binding to G proteins

recruit clathrin and promote internalization of GPCRs

74
Q

unlike PKA and PKC, GRK can only phosphorylate …

A

agonist occupied receptors i.e. receptors bound to ligands

75
Q

signaling mechanism involved in cholera

A

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
Q

Bacterial ADP-ribosylating exotoxins (bAREs) covalently transfer…

A

ADP-ribose moiety of NAD+ to target proteins of infected eukaryotes –> yield nicotinamide and free Hydrogen ion

77
Q

pertussis toxin is anoth example of bacterial toxin with ADP-ribosyltransferase activity. what happens when it ADP-ribosylates alpha-i

A

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
Q

what do outer regions of rods habe

A

membranes with rhodopsin bound to the 11-cis retinal

79
Q

what happens to rods when exposed to light

A

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
Q

in cone cells,retinal is attached to different opsins so that …

A

cis/trans isomerization happens in response to photons with different energy

aka light w diff wavelengths: blue, green, red

81
Q

olfactory GPCRsare coupled to

A

specific g protein: Golf

82
Q

what does Golf activate

A

adenylyl cyclase –> incr cAMP conc –> opens cAMP gated Na channels –> depolarized –>signal sent to brain

83
Q

which two tastes are mediated by a family of three GPCRs that heterodimerize in diff combos

A

umami and sweet

84
Q

all taste receptors are coupled to

A

specific G protein gustducin which activates PLC-beta

BCH Final (5 decks)

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