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Cancer Lectures > Wnt Signalling and Cancer > Flashcards

Wnt Signalling and Cancer Flashcards

1
Q

How many cells does the human body consist of?

A

50-100 E12

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2
Q

What happens at the membrane during signal transduction?

A

Receptor/ligand interaction

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3
Q

What happens in the cytoplasm during signal transduction?

A

Transduction of the signal

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4
Q

What happens in the nucleus during signal transduction?

A

Transcription is switched on/off

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5
Q

What is cancer a disease of?

A

Deregulated signal transduction leading to uncontrolled proliferation

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6
Q

Wnt = Wg + Int-1. What do Wg and Int-1 represent?

A

Wg is drosohila segment polarity gene and Int-1 is the mouse proto-oncogene

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7
Q

In evolution, when did the Wnt pathway appear?

A

At least 650 million years ago

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8
Q

What are the two types of Wnt pathway?

A

Canonical and non-canonical

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9
Q

In canonical Wnt signalling, what happens at the cell membrane?

A

Wnt ligands bind receptors Fz and LRP-5 and LRP-6

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10
Q

What does Fz stand for?

A

Frizzled

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11
Q

What does LRP stand for?

A

Low density lipoprotein receptor-related protein family

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12
Q

In canonical Wnt signalling, what happens in the cytoplasm?

A

Translocation of axin to the membrane and binding to the intracellular tail of LRP
Phosphorylation of Dsh (Dvl)
Accumulation and nuclear translocation of beta-catenin

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13
Q

What does Dsh and Dvl stand for?

A

Dishevelled

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14
Q

In canonical Wnt signalling, what happens in the nucleus?

A

New interactions involving TCF/LEF proteins

Transcriptional repression/transcriptional activation switch

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15
Q

Describe the Wnt family of ligands

A

Consists of 19 glycoproteins which are rich in cysteine

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16
Q

Wnt ligands can be divided into tow groups according to their ability to transform what?

A

Mouse epithelial cell line C57MG

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17
Q

What are the transforming Wnt ligands?

A

1, 3, 3a and 7a

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18
Q

What are the non-transforming or weakly transforming Wnt ligands?

A

2, 4, 5a, 5b, 6, 7b, 11

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19
Q

All Wnt ligands are palmitoylated, what does this mean?

A

They have a covalent attachment of fatty acids making them hydrophobic and poorly soluble in water

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20
Q

What does CRD stand for?

A

Cysteine-rich domain

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21
Q

What family is the Wnt receptor frizzled a member of?

A

The seven-transmembrane-spanning (7TMS) superfamily

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22
Q

What was the first Wnt receptor to be identified?

A

Frizzled

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23
Q

How was frizzled first identified?

A

Through genetic studies in drosophila melanogaster

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24
Q

Describe frizzled proteins

A 
Encoded by about 10 conserved genes in humans and other mammals
Are a small divergent subclass of 7TMS within the G protein-coupled receptor superfamily
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25
Q

What are LRPs specifically required for?

A

Beta-catenin (canonical) signalling

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26
Q

What is required for the association of LRP with Fz?

A

Wnt

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27
Q

What was a result of enforced association when LRP6 was fused with the neurotrophic receptor and Fz with its ligand NT3?

A

Wnt-independent beta-catenin signalling

28
Q

Give an example of a Wnt agonist

A

R-spondin

29
Q

What does R-spondin do?

A

Binds LGR4/5/6 resulting in internalisation and degradation of RNF43 and ZNRF3 E3 ligases

30
Q

What do ZNRF3 E3 ligases do?

A

Ubiquitinate Fz

31
Q

What does LGR stand for?

A

Leucine-rich repeat containing G protein coupled receptors

32
Q

Give an example of a Wnt antagonist

A

Dickkopf

33
Q

What does dickkopf (Dkk) do?

A

Prevents signalling by ninding LRP5/6

34
Q

What is Kremen-2 involved in?

A

Internalisation and degradation

35
Q

What is beta-catenin called in drosophila?

A

Armadillo

36
Q

What is each armadillo repeat in beta-catenin composed of?

A

A pair of alpha helices that form a hairpin structure

Multiple copies of the repeat form an alpha-solenoid structure

37
Q

What do beta-TrCP proteins ensure?

A

Ubiquitination and proteasomal degradation of beta-catenin

38
Q

What does beta-TrCP stand for?

A

Beta-transducin repeats-containing proteins

39
Q

Where does Dvl act in the Wnt pathway?

A

Immediately downstream

40
Q

What do the proteins that interact with Dvl define?

A

Whether canonical or non-canonical pathways are being activated

41
Q

Which Wnt pathway does phosphorylation of Dvl by casein kinase I (CKI) promote?

A

The canonical pathway

42
Q

Is axin an activator or inhibitor of the Wnt pathway?

A

Inhibitor

43
Q

What are the immediate consequences of ligand-receptor interaction?

A

Dvl phosphorylation, Dvl/Fz, and LRP/axin interaction

44
Q

How is the destruction complex inactivated?

A

Using a two-signal (two branches) model of Fz-LRP signalling to beta-catenin
Two branches: Fz/Dvl and LRP/axin talk through axin-Dvl interaction

45
Q

What do axin and APC form and what does this allow?

A

Forms a structural scaffold

Allows GSK-3beta to phosphorylate beta-catenin and axin

46
Q

What is the axin/APc complex able to recruit and what does this allow?

A

CK1 which phosphorylates beta-catenin promoting its phosphorylation by GSK-3beta

47
Q

What is the axin/APC complex central to?

A

The regulation of beta-catenin levels in the cytoplasm of non-stimulated cells

48
Q

What does FAP stand for?

A

Familial adenomatous polyposis

49
Q

What is the biggest part of the scaffold that is found mutated in FAP and sporadic colorectal cancers?

A

APC

50
Q

Where is GSK3beta active?

A

In unstimulated resting cells

51
Q

What does GSK3beta stand for?

A

Glycogen synthase kinase 3beta

52
Q

What does phosphorylation by GSK3beta usually inhibit?

A

Substrates such as beta-catenin

53
Q

What is GSK3beta?

A

A serine/threonine kinase

54
Q

What does GSK3beta have a preference for?

A

Substrates with a pre-existing phospho-ser-thr, four residues C-terminal of the ser/thr site to be phosphorylated

55
Q

What is the role of CK1alpha?

A

Primes beta-catenin for phosphorylation by GSK3beta

56
Q

What is the role of diversin?

A

Recruites CK1alpha to the degradation complex

57
Q

How many Tcfs are there in mammals?

A

Four

58
Q

The beta-catenin/armadillo-binding domain and the DNA-binding HMG box are best conserved, true or false?

A

True

59
Q

Are the C-termini of Tcfs conserved or unique?

A

Unique to one or a few members

60
Q

How many alternative C-termini does splicing result in for hTCF-1 and -4?

A

Two

61
Q

What does alternative promoter usage, as described for hTCF-1 result in?

A

The absence of the beta-catenin binding domain

62
Q

What does HMG stand for?

A

High mobility group box

63
Q

What is HMG?

A

A conserved domain responsible for DNA binding

Interacts with the (A/T)(A/T)CAA(A/T)GG DNA motif

64
Q

What is pangolin?

A

A tcf in drosophila

65
Q

What screen can be carried out to analyse the proteins that interact with Tcfs?

A

Yeast two-hybrid screens

Cancer Lectures (24 decks)

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