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PCL386 > Term Test 1 > Flashcards

Term Test 1 Flashcards

1
Q

Receptor activation of MAPK pathway

A

EGF binds to EGFR cause receptor dimerization and autophosphorylation on cytosolic tyrosines

GRB2 binds to phosphotyrosine via SH2 (also have SH3) domain

SOS1 (GEF) bind to membrane complex

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2
Q

3 key RAS protein in humans

A

KRAS (Kirsten sarcoma virus)
HRAS (Harvey sarcoma virus)
NRAS (neuroblastoma RAS)\

function as binary molecular switch

“off” binds to GDP
“on” binds to GTP

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3
Q

What facilitates RAS activation?

A

SOS (GEF) turn GDP to GTP in RAS (activate)

RAS-GAP turn GTP to GDP (inactivate)

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4
Q

2 RAS effector protein

A

PI3K and RAF (Rapidly accelerated fibrosarcoma) leads to proliferation

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5
Q

Three distinct RAF proteins

A

A-RAF
B-RAF
C-RAF

activated RAF is a phosphorylated dimer

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6
Q

Downstream of RAF signalling

A

RAF (BRAF most active, CRAF then ARAF) kinase activates MEK1 and MEK2

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7
Q

What does MEK1/2 phosphorylate?

A

ERK1 and ERK2 (extracellular signal-regulated kinases)

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8
Q

ERK kinase

A

ERK kinase then dimerizes and enters the nucleus

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9
Q

Scaffold protein (KSR1)

A

maintain three sequential acting kinases as a function complex

RAS -> RAF -> MEK -> ERK

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10
Q

3 downstream effect of ERK1/2

A
  1. proliferation transcription factors
  2. MKs (MAPK-activated protein kinases)
  3. Negative regulators of the MAP kinase pathway (MKP) or (DUSP)
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11
Q

4 transcription factors from ERK

A
  1. Myc (oncogene) activates growth (repress negative regulators of cell cycle and p53)
  2. FOS-JUN (cell proliferation and differentiation)
  3. ETS
  4. FOXO family (induction of apoptosis, p21, p27)
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12
Q

Mutations in MAP kinase pathway

A

KRAS, HRAS, NRAS (colorectal, non-small cell lung, pancreatic, breast cancer)

BRAF (activating oncogenic mutations V600E)

MEK and ERK not mutated

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13
Q

RAS mutation and hotspots

A

maintained in active form (GTP-bound)

hotspots G12, G13, Q61

pancreatic and colorectal cancer

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14
Q

RAF mutations

A

BRAF
mutationally active
expressed in melanoma, glioblastoma, thyroid, lung and colon cancers

V600E substitution of glutamic acid for valine at amino acid 600
mimics phosphorylation (constitutively active kinase activity)
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15
Q

Farnesyl Transferase Inhibitor (FTI)

A

inhibit RAS function

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16
Q

Sorafenib

A

First RAF inhibitor to gain regulatory approval, multi-targeted kinase inhibitor

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17
Q

Vemurafenib

A

BRAF (V600E) selective inhibitor

Resistance to BRAF inhibitors can occur through activating mutations of MEK1/2

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18
Q

MEK inhibitors

A

Trametinhib GSK1120212

use in combination with BRAF inhibitors to treat melanomas

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19
Q

Rapamycin

A

macrolide antibiotic
immunosuppressive
anticancer

inhibit mTOR

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20
Q

mTOR

A

serine/threonine kinase

PI3K related kinase family

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21
Q

4 common mTOR components

A
  1. catalytic mTOR subunit
  2. mammalian lethal with sec-13 protein 8 (mLST8)
  3. DEP domain containing mTOR-interacting protein (DEPTOR)
  4. Tti1/Tel2 complex
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22
Q

2 mTORC1-specific components

A

Raptor

PRAS40

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23
Q

3 mTORC2 specific components

A
  1. Rapamycin insensitive companion of mTOR (Rictor)
  2. mammalian stress-activated map kinase-interacting protein 1 (mSin1)
  3. protein observed with rictor 1 and 2 (protor1/2)
24
Q

Signalling upstream of mTOR

A

TSC1/TSC2
heterodimer
GTPase activating protein (GAP) for RHEB GTPase

25
RHEB
GTP (active) GDP (inactive) GTP-bound form directly interacts with mTORC1 and stimulates its kinase activity TSC1/2 negatively regulates mTORC1 by converting RHEB-GTP to GDP
26
PI3K regulation on mTORC1
AKT phosphorylation inhibits TSC2 and can also activate mTORC1 independently by phosphorylating PRAS40 to cause its dissociation
27
ERK1/2 regulation on mTORC1
ERK1/2 can inhibit TSC1/2 by phosphorylating TSC2
28
AMPK
energy sensor response to hypoxia or low energy state phosphorylates TSC2 increase activity (activating phosphorylation) phosphorylates Raptor, allosteric inhibition of mTORC1
29
Hypoxia sensor
DNA damage response 1 (REDD1) | activates TSC2 function
30
DNA damage sensor
P53 | induce expression of TSC2 and PTEN, cause down-regulation of entire PI3K-mTORC1 axis.
31
Protein Translation control downstream of mTOR
initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) S6 kinase 1 (S6K1) phosphorylation promotes protein synthesis
32
4EBP1
phosphorylation of 4E-BP1 by mTORC1 prevent its binding to eIF4E eIF4E move on to exert effect initiate cap-dependent translation Protein translation and synthesis
33
S6K1
phosphorylation increase mRNA biogenesis, translational initiation and elongation
34
SREBP1 and 2
lipogenesis mTORC1 inhibition reduce SREBP1 and 2 expression lowers expression of lipogenic genes
35
mTORC1 and autophagy
mTORC1 block autophagy, promotes growth directly phosphorylates and suppress ULK1/Atg13/FIP200 to block autophagy
36
mTORC2
activates AKT by phosphorylating Ser473 respond to growth factors such as insulin require PI3K
37
mTORC1 in cancer
mTORC1 is hyperactivated in up to 70% of all human tumors ``` support cancer growth synthesis of protein angiogenesis nutrient uptake metabolism ```
38
3 key proteins regulated by mTOR activation
1. Cell cycle regulators 2. Proangiogenic factors 3. Amino acid and glucose transporters
39
Angiogenesis by mTOR
activation elevates synthesis of HIF-1a and HIF-2a HIF turns on hypoxic stress genes including VEGF and PDGF-B cancer cells secret proangiogenic factors, promote new vessels
40
mTOR in nutrient uptake
mTOR activation increase expression of nutrient transporters LAT and GLUT1 cancer cell can access to nutrients and metabolic fuel support unregulated growth
41
Rapamycin inhibition of mTOR
forms a gain of function complex with FKBP12 | this complex is an allosteric inhibitor of mTOR
42
Rapalogs
Rapamycin derivatives only modest efficacy in tumors negative feedback loops in mTOR contribute to limit therapeutic efficacy for rapalogs BINDS TO FKBP12 and allosteric inhibition
43
S6K-IRS feedback
rapalogs block feedback to turn off PI3K signalling and AKT Rapalogs activate AKT pathway not effective in mTORC2 only destabilize mTORC1
44
Dual mTOR-PI3K inhibition
inhibit mTORC1, mTORC2 and class I PI3K decrease phosphorylation of AKT, S6K1 and 4E-BP1 may hurt normal cells NOVARTIS, EXELIXIS
45
Limitations of Dual mTOR-PI3K inhibition
lack of biomarkers need better understanding of molecular mechanism selection of drug combination therapies more effective and personalized cancer therapy
46
2 frequent mutations of PIK3CA
E535K H1047R Leads to increase PIP3 levels
47
Warburg's effect
Tumor cells convert most of their glucose to lactate even in the presence of adequate oxygen aerobic glycolysis make 4 molecules of ATP for every molecule of glucose consumed metabolism is different in cancer cells tumor cells undergoing rapid growth use glucose extremely inefficiently
48
First step of glycolysis by AKT
Phosphorylate AS160 promotes translocation of vesicles contain GLUT4 to cell surface GLUT4 allows entry of glucose
49
How does PDK1 controls pyruvate entry?
PDK1 phosphorylate PDH PDH cant turn pyruvate into Acetyl-CoA Acetyl-CoA cant go into TCA pyruvate become lactate "Warburg kinase"
50
Anaplerosis
Metabolic pathway used to generate other molecules (replenish TCA intermediates)
51
Glutaminolysis by MYC
MYC increase glutamine transporter SLC1A5 MYC increase first enzyme (GLS) in glutamine metabolism GLS turns glutamine into glutamic acid
52
MYC in glycolysis
makes GLUT1 Lactate dehydrogenase Hexokinase
53
Extracellular Acidification Rate (ECAR)
lactate production
54
Oxygen consumption rate (OCR)
mitochondrial oxidative phosphorylation
55
Gas-Chromatography/ Mass Spectrometry (GS/MS)
allows us to track where heavy carbons end up
56
Isocitrate dehydrogenase 1 (IDH1)
can produce oncometabolites (2-hydroxyglutarate) in IDH mutants IDH mutant cells have a hypermethylation phenotype which blocks DNA DNA differentiation block + proliferation = cancer
57
Nutlins
inhibit p53-MDM2 binding only works on tumor that contains normal or wildtype p53

PCL386 (12 decks)

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