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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 (70 cards)

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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
removal of RTKs vs GPCRs
both use endocytosis to control expression of protein on membrane both utilise clathrin mediated endocytosis CME in RTKs beta arrestin is not involved
26
in RTKs what does endocytosis of RTK depend on (4)
RTK ligand ligand dose - low dose induces CME, high dose something else lol cell type
27
once activated and transphosphorylated, RTKs such as EGFR epidermal growth factor receptor, PDGF platelet derived growth factor, Met can interact with
Cbl
28
what is Cbl
E3 Ubiquitin Ligase which can stick ubiquitin (Ub) molecules to the receptor
29
what is ubiquitin
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
in RTKs, what is needed for clathrin mediated endocytosis to occur
ubiquitin
31
examples of endocytic proteins
epsin Eps15 intersectin-1 Itsn1 (equiv to beta arrestin in GCPRs) allow for invagination
32
what allows for progression of clathrin mediated endocytosis
protein protein interactions
33
difference between GPCRs and RTKs after clathrin coated vesicle is formed intracellularly
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
EGFR, for example, activates (describe pathway)
PLC to convert PIP2 to IP3 and DAG IP3 inc intracellular calcium ions activating CamKII DAG inc PKC
35
RTKs continue to signal even when fusing with early endosome. what is this called?
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
RTK signalling can be regulated ____ and ____
spatially and temporally ie signal changes based on location and time since activation
37
what does the early endosome act to sort receptors for
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
intersectin-1 clinical relevance
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
what can intersectin-1 activate
Cbl Ras directly - RasRafMEKERK
40
what does Cbl do
ubiquitinates EGFR epidermal growth factor receptor to allow machinery to attach and internalise it
41
what does intersectin-1 bind to (signalling protein) (2)
mSos PI3K - activates downstream signalling eventually AKT
42
how is intersectin-1 regulated
Itch E3 Ubiquitin Ligase (similar to Cbl, degradation stickers to intersectin-1) aka dec Itch causes inc Intersectin-1
43
how do we know that Itch and Intersectin-1 directly interact
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
in cells with decreased Itch expression, ERK activation (measured by phosphorylation to pERK) is increased when____ ___ ____
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
RTKs mutate and can cause cancer as they can become
consitutively active - even without agonists present
46
endocytosis may be _____ to allow _____ signalling at the membrane/early endosome
inhibited longer
47
what is the effect of receptor upregulation
more RTKs to activate and produce a stronger signal
48
what drugs bind to EGFR preventing EGF activating receptors
cetuximab/panitumumab
49
what drugs inhibit EGFR transphosphorylation
erlotinib/lapatinib
50
what drug inhibits downstream signalling from EGFR intracellularly
gefitinib
51
what drugs inhibit Raf
debrafenib
52
what drugs inhibit MEK
trametinib
53
compare the structure of RTKs and GPCRs
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
imatinib targets ___ (4) and is used in ____ treatment
PDGFR, Abl, Arg, KIT Chronic myelogenous leukemia
55
gefitinib targets ___ and is used in treating
EGFR oesophageal cancer
56
erlotinib targets ___ and is used in treating
EGFR oesophageal cancer
57
tastuzumab targets ___ to treat
ErbB2 mammary carcinoma
58
cetuximab targets ___ to treat
EGFR head and neck cancers
59
panitumumab targets ___ to treat
EGFR colorectal cancer
60
how does Grb2 exist
as a heterodimer bound to mSos
61
clathrin mediated endocytosis
clathrin communicates between the extra and intra cell environment also needed for endosomal signalling e.g. PKB/Akt or MAPK activation through EGFR
62
Itch E3 Ubiquitin Ligase
sticks ubiquitin onto receptor to mark for degradation, ub also acts as a docking site for other endocytic proteins
63
"sticks ubiquitin onto receptor to mark for degradation, ub also acts as a docking site for other endocytic proteins" examples of proteins - 3
epsin eps15 intersectin - 1
64
intersectin can display
intersectin mediated signalling
65
what occurs after endocytosis
formation of a clathrin coated vesicle, endosomal signalling from part of receptor facing towards EC cell membrane
66
what occurs after endosomal signalling
CCV uncoated, receptors trafficked for degradation or recycling
67
when will a CCV undergo recycling and not degradation
if no Ub attached
68
resensitisation process (after recycling)
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
degradation process occurs via
lysosome
70
intersectin-1 mediated signalling - 2 pathways
activation of Cbl which ubiquinates EGFR, leading to endocytosis bind to mSoS(bound to Grb2) activating MAPK activate Ras directly activating MAPL

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