lec 12 - wnt signalling

Question 1

main paracrine cell signalling pathways

Answer 1

Wnt/Frizzled
Hedgehog
Fgf (RTK)
SMAD - signal transduction (TGF-BMP)

Question 2

functions of Wnt signalling in embryogenesis

Answer 2

gastrulation
body axis formation
limb polarity
muscle development
patterning of nervous system

Question 3

functions of Wnt signalling in regeneration

Answer 3

limb bud
heart
brain

Question 4

diseases related to wnt signalling

Answer 4

melanoma
alzheimers
diabetes
colon carcinoma

Question 5

up regulation of wnt signalling…

Answer 5

leads to cancer

Question 6

down regulation of wnt signalling in the brain..

Answer 6

can cause alzheimers

Question 7

planar cell polarity signalling

Answer 7

induces actin polymerisation
cell polarity
cell migration

Question 8

b-catenin signalling

Answer 8

cell differentiation

cell proliferation

Question 9

wnt-Ca2+ signalling

Answer 9

cell fate acqusition

cell migration

Question 10

structure of mWnt8

Answer 10

350 amino acids

Question 11

modification of Wnt lipid

Answer 11

modified in ER by Porcupine (O-acetyltransferase)

Question 12

secretion of Wnt ligand

Answer 12

Palmitoleic lipidated Wnt is transported in vesicle from ER to golgi

wnt binds to evi and is transported to membrane

Question 13

at the membrane, wnt either….

Answer 13

1- induces fliponi machinery - cytonemes

2- is re-internalised into endosome

Question 14

3 pathways of wnt signalling

Answer 14

planar cell polarity
b-catenin
wnt-Ca2+

Question 15

how are the 3 wnt pathways activated?

Answer 15

by binding a wnt-protein ligand to a frizzled family receptor
- The signal is passed to the dishevelled protein inside the cell

Question 16

frizzled receptor

Answer 16

family of GPCR receptors

7 Transmembrane and a cysteine rich domain (CRD)

when activated, activates dishevelled in cytosol

Question 17

which part of Frizzled does the wnt ligand bind to

Answer 17

the CRD (cysteine rich domain)

Question 18

‘lipid thumb’ of wnt

Answer 18

N-terminal

dominated by Palmitoleic lipid projecting into a groove in the Frizzled CRD

Question 19

low intracelllular conc of beta-catenin

Answer 19

Wnt off state

Question 20

high intracelllular conc of beta-catenin

Answer 20

Wnt on state

Question 21

wnt off state

Answer 21

frizzled receptor and Lrp6 co-receptor endocytosed and recycle back to membrane

beta-catenin degraded in the proteosome (phosphorylated and ubiquitilated)

Question 22

how is beta-catenin degraded

Answer 22

in the proteosome

phosphorylated by GSK-3B
released from the beta-catenin destruction complex
ubiquitilated by B-TRCP

Question 23

beta-catenin destruction complex

Answer 23

3 structural proteins:

• APC
• Dishevelled
• Axin 1

Kinase:
- GCK-3Beta

Question 24

wnt on state

Answer 24

formation of ligand-receptor complex
recruitment of components of beta-catenin destruction complex to the plasma membrane
deactivation of the destruction complex
beta-catenin translocates to nucleus
beta-catenin binds to DNA and transcription can occur

Question 25

formation of ligand-receptor complex

Answer 25

Wnt binds to Frizzled receptor and Lrp6 co-receptor

Lrp6 is phosphorylated

Question 26

recruitment of components of beta-catenin destruction complex to the plasma membrane

Answer 26

frizzled receptor binds to Dishevelled
Lrp6 co-receptor binds to Axin 1

both structural proteins are phosphorylated

Question 27

deactivation of the beta-catenin destruction complex

Answer 27

conformational change of Axin1
blocks GSK-3Beta enzyme

therefore no phosphorylation/ubiquitilation of B-catenin

Question 28

which intestinal cells express Wnt

Answer 28

paneth cells

Question 29

what creates specificity in wnt pathway

Answer 29

interaction with co-receptors