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342 > regulation of RTK/ receptor tyrosine kinase signalling > Flashcards

regulation of RTK/ receptor tyrosine kinase signalling Flashcards

mind maps of these pathways would help esp to compare GPCR - dont need to memorise other than rasrafMEKERK

1
Q

RTKs have a ______ structure compared to GPCRs

A

very different

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2
Q

the structure of RTKs

A

single transmembrane alpha helix (GPCRs have 7 transmembrane domains)

extracellular ligand binding domains

protein tyrosine kinase domain intracellularly (TKD)

C terminal tail

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3
Q

how many known RTKs in humans

A

58, 20 subfamilies

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4
Q

subfamily ErbB includes which members (4)

A

EFGR (ErbB1)
HER2 (ErbB2) - breast cancer
ErbB3
ErB4

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5
Q

subfamily Met includes which members (2)

A

Met (colorectal cancer)
Ron

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6
Q

subfamily VEGF includes which members (3)

A

VEGFR1- vascularisation
VEGFR2
VEGFR3

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7
Q

subfamily PDGF includes which members (3)

A

PDGFalpha
PDGFbeta
CSF1r

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8
Q

what can result from genetic changes/ abnormalities that alter activity, abundance, cellular distribution or regulation of RTKs

A

numerous diseases e.g. cancer, diabetes, inflammation, severe bone disorders, atherosclerosis, angiogenisis

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9
Q

most RTK endogenous ligands are

A

soluble growth factors

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10
Q

binding of growth factors/ ligands to RTKs cause what

A

receptor dimerisation

similarly to GCPRs but rtks defo trans, gpcrs might trans

differently, can oligomerise - form cluster

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11
Q

role of tyrosine kinase domain on C terminal of RTKs

A

phosphorylates tyrosine residues on other RTK - transphosphorylation

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12
Q

what is transphosphorylation

A

one monomer (RTK) acts as a tyrosine kinase domain, phosphorylates other monomer (RTK)

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13
Q

what do newly transphosphorylated residues do

A

act as docking sites for adaptor proteins that activate downstream signal transduction pathways by binding to RTK

e.g. growth receptor bound protein 2 Grb2

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14
Q

some RTKs such as ______ will spontaneously form dimers in absence of ligands

A

EGFR epidermal growth factor receptor

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15
Q

what is unique about RTKs such as EGFR

A

form spontaneous dimers in absence of ligands but do not undergo transphosphorylation, no signal transduction events until ligand binds

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16
Q

in absence of ligands are TKDs active

A

no - dimer may be formed but do not undergo transphosphorylation, no signal transduction events

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17
Q

what occurs when RTK is activated by an agonist

A

RTKs dimerise

undergo transphosphorylation

transphosphorylated RTKs act as adaptor sites for adaptor proteins, allow them to interact

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18
Q

example of adaptor protein

A

Grb2

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19
Q

what occurs after Grb2 interacts with transphosphorylated RTK

A

Gbr2 is bound to mSos

mSos is GEF so can exhange GDP for GTP

this activates Ras

activates downstream signalling e.g. Ras Raf MEK ERK/ MAPK signal transduction pathway - tranc/lation

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20
Q

what is mSos

A

guanine nucleotide exchange factor (GEF)

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21
Q

activated EGFR can directly activate ___ which converts ____ to ____ and ____

A

PLC phospholipase C
PIP2
IP3
DAG diacylglycerol

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22
Q

what does IP3 activation cause

A

inc intracellular calcium level

activation of calmodulin-dependent protein kinase II (CaMKII) and protein kinase C PKC

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23
Q

activation of calmodulin-dependent protein kinase II (CaMKII) and protein kinase C PKC is caused by what

A

inc intracellular calcium level e.g. through IP3 and DAG activation

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24
Q

in healthy cells recceptors are internallised and removed from membrane preventing

A

uncontrolled signalling

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25
Q

removal of RTKs vs GPCRs

A

both use endocytosis to control expression of protein on membrane

both utilise clathrin mediated endocytosis CME

in RTKs beta arrestin is not involved

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26
Q

in RTKs what does endocytosis of RTK depend on (4)

A

RTK
ligand
ligand dose - low dose induces CME, high dose something else lol
cell type

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27
Q

once activated and transphosphorylated, RTKs such as EGFR epidermal growth factor receptor, PDGF platelet derived growth factor, Met can interact with

A

Cbl

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28
Q

what is Cbl

A

E3 Ubiquitin Ligase which can stick ubiquitin (Ub) molecules to the receptor

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29
Q

what is ubiquitin

A

small protein

mark for degradation of proteins in cells

act as docking site for endocytic proteins to work on receptor, allowing clathrin mediated endocytosis

30
Q

in RTKs, what is needed for clathrin mediated endocytosis to occur

31
Q

examples of endocytic proteins

A

epsin
Eps15
intersectin-1 Itsn1 (equiv to beta arrestin in GCPRs)

allow for invagination

32
Q

what allows for progression of clathrin mediated endocytosis

A

protein protein interactions

33
Q

difference between GPCRs and RTKs after clathrin coated vesicle is formed intracellularly

A

RTKs continue to signal even when fusing with early endosome

early endosome then trafficks receptor to degradation and recycling pathways (same) via proteosome or lysozome

34
Q

EGFR, for example, activates (describe pathway)

A

PLC

to convert PIP2 to IP3 and DAG

IP3 inc intracellular calcium ions activating CamKII

DAG inc PKC

35
Q

RTKs continue to signal even when fusing with early endosome. what is this called?

A

endosomal signalling - can activate new different pathways e.g. Akt and MAPK activation via epidermal growth factor receptor in endosomes

therefore endocytosis important for switching signal on as well as off

36
Q

RTK signalling can be regulated ____ and ____

A

spatially and temporally
ie signal changes based on location and time since activation

37
Q

what does the early endosome act to sort receptors for

A

for recycling back to the membrane to signal anew - pH in early endosome promotes dissociation of growth factors from receptor and dephosphorylates it (same as GPCR)

for degradation via lysosome to reduce number of receptors on membrane avaliable for signalling aka downregulation (same as GPCR)

38
Q

intersectin-1 clinical relevance

A

participates in human cancers e.g. neuro/glioblastomas

downregulation associated with lung injury

alterations found in neurodegenerative disease e.g. down syndrome and Alzheimer’s disease

39
Q

what can intersectin-1 activate

A

Cbl

Ras directly - RasRafMEKERK

40
Q

what does Cbl do

A

ubiquitinates EGFR epidermal growth factor receptor to allow machinery to attach and internalise it

41
Q

what does intersectin-1 bind to (signalling protein) (2)

A

mSos
PI3K - activates downstream signalling eventually AKT

42
Q

how is intersectin-1 regulated

A

Itch E3 Ubiquitin Ligase (similar to Cbl, degradation stickers to intersectin-1)

aka dec Itch causes inc Intersectin-1

43
Q

how do we know that Itch and Intersectin-1 directly interact

A

purified Itch protein bound to GST (GST-Itch) can be mixed with cell lysate to ‘pull down’ Intersectin-1, shows what has bound and what hasn’t

44
Q

in cells with decreased Itch expression, ERK activation (measured by phosphorylation to pERK) is increased when____ ___ ____

A

stimulated with agonist

aka measuring activation of MAPK pathway - shows inc phosphorylation and inc activation, inc expression of intersectin-1 which inc activation of MAPK

45
Q

RTKs mutate and can cause cancer as they can become

A

consitutively active - even without agonists present

46
Q

endocytosis may be _____ to allow _____ signalling at the membrane/early endosome

A

inhibited
longer

47
Q

what is the effect of receptor upregulation

A

more RTKs to activate and produce a stronger signal

48
Q

what drugs bind to EGFR preventing EGF activating receptors

A

cetuximab/panitumumab

49
Q

what drugs inhibit EGFR transphosphorylation

A

erlotinib/lapatinib

50
Q

what drug inhibits downstream signalling from EGFR intracellularly

51
Q

what drugs inhibit Raf

A

debrafenib

52
Q

what drugs inhibit MEK

A

trametinib

53
Q

compare the structure of RTKs and GPCRs

A

rtk - single transmembrane alpha helix

EC ligand binding domain

IC TK domain

gpcr- 7 barrel shaped transmembrane helices

EC ligand binding domain

IC G protein interaction domain

54
Q

imatinib targets ___ (4) and is used in ____ treatment

A

PDGFR, Abl, Arg, KIT

Chronic myelogenous leukemia

55
Q

gefitinib targets ___ and is used in treating

A

EGFR

oesophageal cancer

56
Q

erlotinib targets ___ and is used in treating

A

EGFR

oesophageal cancer

57
Q

tastuzumab targets ___ to treat

A

ErbB2

mammary carcinoma

58
Q

cetuximab targets ___ to treat

A

EGFR
head and neck cancers

59
Q

panitumumab targets ___ to treat

A

EGFR

colorectal cancer

60
Q

how does Grb2 exist

A

as a heterodimer bound to mSos

61
Q

clathrin mediated endocytosis

A

clathrin communicates between the extra and intra cell environment

also needed for endosomal signalling e.g. PKB/Akt or MAPK activation through EGFR

62
Q

Itch E3 Ubiquitin Ligase

A

sticks ubiquitin onto receptor to mark for degradation, ub also acts as a docking site for other endocytic proteins

63
Q

“sticks ubiquitin onto receptor to mark for degradation, ub also acts as a docking site for other endocytic proteins” examples of proteins - 3

A

epsin
eps15
intersectin - 1

64
Q

intersectin can display

A

intersectin mediated signalling

65
Q

what occurs after endocytosis

A

formation of a clathrin coated vesicle, endosomal signalling from part of receptor facing towards EC cell membrane

66
Q

what occurs after endosomal signalling

A

CCV uncoated, receptors trafficked for degradation or recycling

67
Q

when will a CCV undergo recycling and not degradation

A

if no Ub attached

68
Q

resensitisation process (after recycling)

A

acidic pH in early endosomes, which promotes dissociation of ligands from receptor

aka the receptor is dephosphorylated, returned to plasma membrane, ready to bind to new ligand

69
Q

degradation process occurs via

70
Q

intersectin-1 mediated signalling - 2 pathways

A

activation of Cbl which ubiquinates EGFR, leading to endocytosis

bind to mSoS(bound to Grb2) activating MAPK

activate Ras directly activating MAPL

342 (20 decks)

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