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B301 > WS: Notch Signalling > Flashcards

WS: Notch Signalling Flashcards

1
Q

Outline the sequence of events in canonical notch signalling:

A
  • S1 cleavage of receptor in golgi (Furin)
  • -> receptor fragments remain associated and are transported to cell surface
  • Notch ligand on adjacent cell interact -> S2 cleavage by members of ADAM family of enzymes (ADAM10 or ADAM17) leaving the NCTF ‘stump’ in the membrane -> subsequent S3/S4 cleavage by gamma secretase complex
  • NICD (notch intracellular domain) translocates to nucleus, displace co-repressor from CSL TF
  • CSL-NICD recruits MAML and a coactivator
  • Gene repression (differentiation + proliferation)
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2
Q

How are human notch receptor typically modified? Give examples of 3 of these enzymes

A
  • Post translational modification by ‘Fringe’ glycosylases
  • Determines which ligand the receptor interacts with
  • Fringe glycosylases: Radical, manic, lunatic
  • Takes place in golgi apparatus
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3
Q

List the various mammalian notch ligands, with 2 key extracellular and 1 key intracellular domain:

A
  • Jagged 1 and 2
  • DII 1, 3 and 4
  • Differ by domain structure
  • I-C: PDZ (post synaptic density signalling)
  • E-C: DSL, EGF repeats
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4
Q

What is the active component of the gamma secretase complex?

A
  • Aspartyl proteinase called Presenilin
  • Require a water molecule -> issue in hydrophobic environment and area of doubt in field
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5
Q

What hallmarks of cancer is Notch signalling involved in?

A
  • Cell proliferation
  • EMT
  • CSC maintenance
  • Angiogenesis
  • Resistance to traditional chemo and radiotherapy
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6
Q

What are ADAM proteins?

A
  • A disintegrin and metalloproteinases
  • Proteolytic enzymes involved in shedding of membrane bound proteins, GFs etc
  • Generally activated by proprotein convertases which cleave the pro-domain
  • ADAMs act as regulators of cell proliferation and may also be involved in cancers; potential prognostic markers in case of lung cancer
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7
Q

Give the 4 components of the gamma-secretase complex:

A
  • Presenilin (including catalytic site)
  • Nicastrin (Gatekeeper which blocks access to substrates with larger ectodomains)
  • Aph-1
  • Pen-2
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8
Q

Outline the role of Notch signalling:

A
  • Cell fate determination
  • Proliferation
  • Apoptosis
  • Adult tissue homeostasis
  • Embryonic development
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9
Q

By what mechanisms is S2 cleavage by ADAMs enacted?

A
  • Notch has a NRR (negative regulatory region) which contains structural machinery for MMP resistance in absence of ligand
  • When ligand binds, activation switch is exposed -> ADAM10/17 able to cleave
  • This occurs due to mechanical pulling force from the ligand as it is internalised in endocytosis
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10
Q

Structure of Notch receptors:

A
  • I-C: PEST (degradation signals), TAD (only in certain members), ANK, NLS, RAM (associates with TFs in nucleus)
  • E-C: NRR (HD, LNR), EGF-like repeats(ligand interaction), SP (signal peptide)
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11
Q

What sets notch signalling apart from other pathways covered in this module?

A
  • Relatively irreversible
  • The receptor itself is irreversibly cleaved to enact transcriptional activation
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12
Q

2 examples of Notch target genes:

A
  • Hes family
  • Hey family
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13
Q

JAG1 in HCC:

A
  • Found to be upregulated in majority of hepatocellular carcinoma cases
  • Oncogenic role
  • Notch signalling via JAG1 upregulate osteopontin (OPN) which is a key driver of extra-hepatic HCC metastasis
  • RUNX3 is downregulated in many HCCs; usually opposes Notch signalling
  • JAG1 is also linked with therapy resistance
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14
Q

What pathways does JAG1/Notch signalling crosstalk with during oncogenic activities?

A
  • ILs
  • TGF-B
  • Hippo
  • Wnt/B-catenin
  • All contributes to cancer development through regulation of behaviour of tumour cells and cells in the TME
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15
Q

How can JAG1 be targeted as a therapeutic strategy against cancer? (4 novel and 1 historical including key issue)

A
  • JAG1 gene silencing by lentivectors containing JAG1 siRNA or expression of certain miRNAs
  • Interfering with signalling cascade (e.g. upregulating Neur1/inhibiting Mib1, treating cells with ‘dynasore’ which inhibits dynamin and thus promotes cell apoptosis, or use of antibodies against JAG1-Notch interactions)
  • Most commonly used strategy is GSI (gamma secretase inhibitor) -> serious issues with toxicity
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16
Q

What two E3 ligases are required for JAG1 endocytosis?

A
  • Neuralized1 -> negatively affects Notch signalling
  • Mindbomb-1 -> positively affects Notch signalling
  • Dynamin is also important for JAG1 endocytosis and is an endocytic adaptor protein
17
Q

Notch signalling and apoptosis:

A
  • Prevents apoptosis through p53 inhibition via the PI3K-Akt pathway
  • Alt: NFkB activation
  • -> Upregulation of anti-apoptotic proteins (survivin, Bcl2)
  • Notch inhibition is shown to increase expression of pro-apoptotic proteins
18
Q

Notch signalling in angiogenesis:

A
  • Notch signalling has been shown to stimulate angiogenesis (linked with DLL-4)
  • e.g. Head and Neck SCC
19
Q

TSG activity of Notch in BCC:

A
  • Notch signalling via Hh pathway results in enhanced Gli expression, which controls SC proliferation
  • Inhibited by PTCH1
  • Can also act as a TSG through Wnt signalling (inhibition or deletion associated with increased beta-catenin expression)
20
Q

Biphasic action of Notch signalling in small cell lung cancer:

A
  • Downregulates Slug, Snail, Vimentin (EMT TFs) whilst upregulating E-cadherin -> TSG by preventing EMT
  • Preventing Cdk-inhibition (decreased p21 expression)
20
Q

Biphasic action of Notch signalling in non-small cell lung cancer:

A
  • Upregulation of survivin, IGF-1R -> tumour growth and survival
  • However, DLL4 overexpression reduces survival rates
20
Q

List key therapies against Notch signalling:

A
  • Thapsigargin (S1 inhibitor via malfunction of SERCA pump)
  • Notch receptor antibodies
  • Antibodies targeting JAG1, DLL3, DLL4
  • GSI and GSM (against gamma secretase complex)
  • S2 inhibitors
21
Q

NOTCH3 and ND disease:

A
  • Notch signalling is known to impact development of neurodegenerative disease including alzheimer’s and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
  • NOTCH3 mutations are known to cause CADASIL
  • Mutations in presenilin are common in AD
  • Downs syndrome is a major risk factor for ND disease as amyloid precursor protein is upregulated -> drives competitive inhibition of Notch-1 cleavage by presenilin-1 enzyme

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