Wnt Signalling

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  • Created by: Sarah
  • Created on: 01-03-18 15:23
what is the phenotype when you lose wnt/wingless/int?
get all denticle belts lose naked cuticle no segment polarity
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how do they know that the wnt signalling pathway is ancient?
its found in all metazoans including sponges
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what are other genes involved in the formation of wnt?
porcupine, wntless (and HSPGS but poss diffusion)
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why did they come up with the name wnt?
mixture (amalgam of wingless (drosophila gene) and int (a mouse homologue of wingless thats a proto-oncogene)
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how did they find the int-1 gene?
it was activated by a nearby integration of the mammary tumour virus which activated the gene and was an important step in forming the tumour
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what did null alleles of wingless do?
disrupt segment polarity in the embryo (denticles and naked cuticle)
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why are there more genes for wnt in vertebrates?
there was a number of genome duplications which duplicated genes
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what is wntless needed for?
for wnt to be at the plasma membrane and be released from the plasma membrane
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how can wnt be released?
needs to form multimers or loaded onto lipoprotein particles + HSPGS needed for it to form
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how did they show that in drosophila direct cell contact and not diffusion is less important in wnt signalling?
made forms of wnt that could not be released from the cell just stuck to the cell but it was sufficient to create a normal fly
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why does wnt need lipoproteins/multimers to be released?
not soluble in water due to fatty modifications
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which 2 modifications does the wnt ligand undergo?
palmitoylation and palmitoleic acid
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where is wnt modified (what aas)?
cysteine 77 and serine at 209
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briefly describe how wnt is formed?
protein transcribed and has an N terminal signal leader sequence which gets cleaved off to enter into the secretory pathway then modified at cysteine+serine by palmitoylation then palmitoleic acid
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what is acyl transferase porcupine required for?
the post translational modification (fatty ones) of wnt protein to enable their transport, secretion and activity
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what are the drosophila receptors for the wnt signal?
frizzled 1-4, arrow
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what are the human wnt receptors?
Fz1-10, LRP5 and 6
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what is the nuclear factor that drives gene transciption from wnt signalling in drosophila?
armadillo/beta catenin
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what is the nuclear factor that drives gene transciption from wnt signalling in drosophila?
beta catenin
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the wnt receptor frizzled is made up of how many TM protein?
7
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what is the wnt receptor made up of?
7 TM protein frizzled and LRP/arrow
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what does LRP stand for? what does this fit with?
lipoprotein receptor related protein- fits with fact people think wnt is loaded onto lipoprotein particles to diffuse away from cells
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what is the cysteine rich domain (CRD)?
the long N terminal extension of the frizzled receptor that wnt binds to
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what does wnt bind to?
frizzled CRD domain and LRP/arrow by the EC domain
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what kind of protein is LRP/arrow?
a single pass transmembrane protein
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when is signalling of the wnt pathway really thought to be iniated?
when you bring the 2 receptors frizzled and LRP/arrow together
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why is dickkopf1 used experimentally?
can be used to down regulate the wnt pathway. Overexpressing Dkk1 downregulates the signal
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how does dickkopf1 downregulate the wnt signalling pathway?
binds to LRP/arrow + couples it to another TM protein kremen which takes up arrow, removes it from the plasma membrane and causes it downregulation. Without arrow/LRP wnt wont work
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why is beta catenin at a low level with no wnt signalling?
its being broken down all the time
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how does wnt signalling change the amount of free cytoplasmic beta catenin?
it increases it, breakdown of BC doesn't work anymore
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how often is beta catenin produced in the cell?
continously
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what makes up the destruction complex?
axin, APC, CK1 and GSK B
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what kind of protein is axin?
a scaffold protein
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how does the destruction complex cause degradation of Beta catenin?
BC binds to complex 1st phos by CSK then num of phos by GSK3 B. Phos means its recognised by a ubiquitination complex containing slimb- ubiquitination of B then targetted by proteasome
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what is slimb called in vertebrates?
beta Trcp
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what does slimb do?
ubiquitination of beta catenin
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what is groucho?
a negative regulator of transcription
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what happens in the pathway when wnt is present?
arrow+frizzled come together-> Dsh comes to it+is phos-> destruction complex to receptor complex->more phos of arrow more BS for Destruction complex->slimb is lost. Get backlog as BC in DC not getting ubiquinated new BC not phos-> enters nucleus tran
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what is wnt target genes usually repressed by?
TCF (DNA binding factor) + groucho (-ve regulator of transcription)
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what happens to the repressors as a result of BC accumulation?
groucho is replaced from TCF and BC can then act as a transcriptional activator
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what is essential for beta catenin to be recognised by ubiquitin ligase complex?
phosphorylation first by CK1 then GSK3
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The ubiquitin ligase complex conatins slimb/trpc why?
it is the substreate recogintion part recognises beta catenin
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what kind of repeats does the F box protein contained in TRCP/slimb have
WD40 repeats
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what do the WD40 repeats do?
recognise the phosphorylated bits of BC for degradation. Only then can it recognise and add ubiquitin to it
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Other cards in this set

Card 2

Front

how do they know that the wnt signalling pathway is ancient?

Back

its found in all metazoans including sponges

Card 3

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what are other genes involved in the formation of wnt?

Back

Preview of the front of card 3

Card 4

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why did they come up with the name wnt?

Back

Preview of the front of card 4

Card 5

Front

how did they find the int-1 gene?

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