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Advanced Cell Biology > Lecture 17 - Wnt Network > Flashcards

Lecture 17 - Wnt Network Flashcards

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1
Q

Paracrine cell signalling

A

Cells that are near one another communicate through the release of chemical messengers (ligands that can diffuse through the space between the cells)
This type of signalling, in which cells communicate over relatively short distances, is known as paracrine signalling

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2
Q

Int experiments - Roel Nusse 1982

A

Retroviral insertion of wnt randomly into genome of mice
Leads to downstream gene activation
Identification of Int1 (insertion 1)

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3
Q

Proto oncogene

A

A normal gene that could become an oncogene due to mutations or increased expression
Proto-oncogenes code for proteins that help to regulate the cell growth and differentiation

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4
Q

Oncogene

A

A gene that has the potential to cause cancer

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5
Q

Wingless experiments - Volhard and Weischaus 1980

A

Knock out wing genes in fruit flies
Gene identified as ‘wingless’
Wingless and Int = orthologs

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6
Q

Wingless + Int

A

Wnt

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7
Q

The Wnt pathway summary

A

Wnt -> Dvl -> GSK3 -> b-catenin -> TCF

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8
Q

Wnt pathway functions

A

Embryogenesis (wing development in drosophila)

Disease (Oncogene in mice)

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9
Q

The Wnt/b-catenin pathway is

A

Highly conserved

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10
Q

Wnt regulates

A

Cell proliferation
Cell fate
Apoptosis

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11
Q

Wnt can influence the development of

A

An entire organism

mutations at certain stage of development can induce a second head in xenopus

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12
Q

Wnt ‘network’ in 2017

many pathways

A

Embryogenesis
Regeneration
Disease

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13
Q

Wnt embryogenesis

A 
Body axis formation
Patterning of nervous system (anterior posterior)
Neural crest induction
Hair follicle growth
Limb polarity
Muscle development
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14
Q

Wnt regeneration

A

Limb bud
Heart
Brain

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15
Q

Wnt diseases

A 
Colon carcinoma
Mamma carcinoma
Melanoma
Alzheimers
Diabetes
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16
Q

3 pathways in the Wnt signalling network

A
  1. Planar cell polarity signalling (cell polarity and migration)
  2. b-catenin signalling (cell differentiation and proliferation)
  3. Wnt Calcium signalling (cell fate and migration)

Pathways interact

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17
Q
  1. Planar cell polarity pathway
A

Tells cells where to go
Uses Frizzled family GTpases
e.g. neural crest cells

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18
Q

Frizzled

A

A family of G protein-coupled receptor proteins that serves as receptors in the Wnt signaling pathway
When activated, Frizzled leads to activation of Dishevelled in the cytosol

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19
Q

Dishevelled

A

Dsh (Dvl in mammals) is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors
It takes its name from its initial discovery in flies, where a mutation in the dishevelled gene was observed to cause improper orientation of body and wing hairs

Dishevelled plays important roles in both the embryo and the adult, ranging from cellular differentiation and cell polarity to social behavior

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20
Q
  1. b-catenin signalling pathway
A

Wnt molecule binds to a receptor
Deactivates a protein complex
b-catenin is translocated to the nucleus
Activates gene transcription

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21
Q

The 3 Wnt pathways

A

Interact with each other

Pathways 1 and 2 repress each other

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22
Q

Wnt ligand structure

A

350 a.a
22 cysteines (disulfide bridges important for form of protein)
Serine 187 (palmitoleic acid)
Asparagin 87 + 298 (glycosylation)

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23
Q

Wnt ligand numbers

A

19 ligands
10 Frizzled receptors
5 co receptors

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24
Q

Two post translational modifications on Wnt ligands

A

Palmitoylation

Glycosylation

25
Q

Palmitoylation occurs at

A

Serine 187

26
Q

Glycosylation occurs at

A

Asparagine 87 and 298

27
Q

The Wnt protein look like a

A

Hand
Palmitoleic acid at thumb
Glycosylations in the palm

28
Q

The presence of the hydrophobic palmitoleic acid

A

Makes it hard to diffuse into the cell

29
Q

Production of the Wnt ligand

A
  1. Wnt is lipid modified by the ER by O-acetyltransferase (Porcupine)
  2. Palmitolated Wnt is transported in vesicles to the Golgi by p24
30
Q

Porcupine

A

Enzyme that modifies Wnt (O acetyltransferase)

Allows transport, secretion and activity

31
Q

Without porcupine Wnt cannot be

A

Palmitoylated

32
Q

Secretion of the Wnt ligand

A

Transported from the Golgi by Evi/Wntless
Wnt loaded onto cytonemes (signalling filopodia)
Wnt is packaged in exosomes (mutli vesicular bodies)
The released

33
Q

Evi/Wntless

A

Chaperone type protein that binds Wnt

An important checkpoint

34
Q

Mutli vesicular bodies

A

A specialised subset of endosomes that contain membrane-bound vesicles
These vesicles form by budding into the lumen of the MVB
The content of MVBs can be degraded, via fusion with lysosomes, or released into the extracellular space, via fusion with the plasma membrane

35
Q

Once released, Wnt exosomes can travel

A

Through the entire body

36
Q

Interaction of Wnt and Frizzled

A

Wnt binds to the CRD on Frizzled as a monomer

Thumb and finger of Wnt bind to the CRD

37
Q

Frizzled has a

A

7 TM domain and a CRD (cysteine rich domain)

38
Q

The ‘thumb’ of Wnt (palmitoleic site) is projected into a

A

Groove in the Frizzled CRD

39
Q

Specific Wnt ligands have

A

Very specific functions
e.g. Wnt 4 mutants have non functional kidneys
Wnt 1 mutants have no mid brain

40
Q

Specific Wnt ligands bind to

A

Specific Frizzled receptors

41
Q

When Wnt is NOT bound to Frizzled

A
  1. Fzd Receptors continually endocytosed at the membrane (recycled)
  2. The protein b-catenin is bound by a ‘destruction complex’ with protein kinases CK1y and GSK3-b
  3. The protein kinases phosphorylate b-catenin, targeting for degradation in the proteosome (no free b-catenin in nucleus)
  4. In the absence of b-catenin, transcriptional co repressors bind to TCF transcription factors to prevent expression of certain genes
42
Q

The beta catenin destruction complex

A

APC + Dvl + Axin1 + GSK3b

All structural proteins

43
Q

hen Wnt IS bound to Frizzled

A
  1. Signal transmitted by Fzd and LRP
  2. Activation of Fzd and LRP causes CK1y and GSK3-b to associate with membrane
  3. Protein kinases phosphorylate the tail of of LRP
  4. Dishevelled and Axin associate with cytoplasmic tails of Fzd and LRP
  5. This prevents the formation of the destruction complex
  6. Beta catenin increases in the cytoplasm
  7. Beta catenin moves into the nucleus
  8. Catenin binds to TCF, displacing repressors
    Target genes expressed
44
Q

beta catenin is the

A

Key effector of Wnt signalling

45
Q

Beta catenin can

A
  • interact with scaffold proteins Axin1 and APC
  • be phosphorylated by GSK3b
  • be ubiquitinated by bTRCP
  • can translocate to the nucleus to regulate transcription
  • further role in cell adhesion with cadherin
46
Q

Ubiquitination

A

Addition of ubiquitin to a substrate protein
Ubiquitination affects proteins in many ways: it can mark them for degradation via the proteasome, alter their cellular location, affect their activity, and promote or prevent protein interactions

47
Q

Phosphorylation

A

Activity of proteins can be altered after they are formed

A phosphate group ( PO3−4 ) is added to a protein by specific enzymes called kinases

48
Q

Cytoneme

A

Thin, cellular projections that are specialized for exchange of signaling proteins between cells
Cytonemes emanate from cells that make signaling proteins, extending directly to cells that receive signaling proteins

49
Q

Advantages of a ‘handbreak on’ system

A

Keeping all components in place with the ‘lock on’
System ready to go
Wnt ligand receptor releases the ‘hand break’
Very fast responses

50
Q

Wnt signalling is

A

Very fast

Activates transcription within minutes

51
Q

Wnt special features

The negative feedback loop of Axin2

A

Wnt signalling activates the transcription of Axin
Axin is an inhibitor of Wnt/b-catenin signalling
Does this via negative feedback loop
Ribosyltransferase Tankyrase mediates poly-ADP ribosylation of Axin = degradation
Chemical inhibitors of Tnks block Wnt signalling (drug therapy using Axin)

52
Q

Axin is an

A

Inhibitor of wnt/catenin pathway

53
Q

Wnt is difficult to synthesise for regenerative medical applications so

A

Wnt surrogates are made instead

all you have to do is cause Fzd to associate with LRP

54
Q

Wnt catenin signalling in diseases

A

10 billion cells are lost from gut villi daily

Wnt signalling controls regeneration of stem cells into Goblets and enterocytes

55
Q

Wnt ligands are expressed in intestinal

A

Paneth cells and stroma cells

56
Q

The APC protein is a

A

Tumour suppressor gene

57
Q

When the APC or beta catenin genes are mutated

A

Colon cancer occurs

58
Q

In cancer, APC can no longer

A

Keep beta catenin out of the nucleus

59
Q

Inside the nucleus beta catenin

A

Causes uncontrolled cell proliferation

Advanced Cell Biology (31 decks)

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