Hedgehog and Wnt Signalling

Question 1

What are the components of the destruction complex?

Answer 1

B-catenin, APC, GSK3, CKI, Axin, Dvl

Question 2

Which molecule is incorporated into the destruction complex following the phosphorylation of B-catenin?

Answer 2

B TrCP

Question 3

What happens once B TrCP is incorporated into the destruction complex?

Answer 3

It is ubiquitinated and leads to the proteasomal degradation of B-catenin

Question 4

What happens at the membrane when Wnt is present?

Answer 4

Wnt binds to receptors on Frizzled leading to the phosphorylation of LRP5

Question 5

Outline the Wnt signalling pathway once LRP5 has been phosphorylated

Answer 5

1. LRP5 leads to translocation of the destruction complex to the membrane
2. Dvl is activated
3. This inhibits the complex, preventing phosphorylation of B-catenin
4. This prevents incorporation of B TrCP into the complex and hence prevents its ubiquitination
5. B-catenin can’t be degraded by the proteasome
6. B-catenin levels rise and translocate into the nucleus
7. In the nucleus they displace Grucho from TCF and bind to TCF
8. Binding of B-catenin to TCF causes Wnt target genes to be switched on, resulting in patterning, growth and proliferation

Question 6

What are the roles of Wnt signalling?

Answer 6

DV patterning
Segmentation
Growth and proliferation

Question 7

How can Wnt signalling lead to cancer?

Answer 7

Mutations in APC leads to an increase in B-catenin levels, loss of function of the destruction complex which in turn leads to too much proliferation

Question 8

What can mutations in LRP5 lead to?

Answer 8

Bone disease

Question 9

Outline the stages of the inactivated Hedgehog signalling pathway

Answer 9

Patched inhibits Smoothened
Smo is degraded by the proteasome
Ci is bound to Cos2 and Fu (SuFu acts as a repressor to Fu)
When Smo is degraded, PKA, CKIalpha and GSK3 phosphorylate Ci which converts Ci to its repressed form
CiR is translocated into the nucleus and it blocks transcription of Ci target genes

Question 10

Outline the stages of the activated Hedgehog signalling pathway

Answer 10

Hh (using ihog and Boi) inhibits the inhibitory effect of Ptc on Smo
This allows a cellular component of Smo to prevent the phosphorylation of Ci by instead being phosphorylated by PKA and CKIalpha as well as another molecule, Gpra2
When Ci is no longer being phosphorylated it is converted into its active form
CiA is translocated into the cell where it can switch on Ci target genes that lead to cell patterning and differentiation

Question 11

What disease does a lack of Hh lead to?

Answer 11

Holoprosencephaly (cylopamine induced)

Question 12

What is the effect of cyclopamine on the Hh pathway?

Answer 12

It blocks Shh signalling

Question 13

What disease will too much Hh lead to?

Answer 13

Polydactly

Question 14

Which cancers may be caused by gain of Hh signalling?

Answer 14

Basal cell carcinoma, medulla blastoma, rhabdomyosarcoma

Question 15

Which cancers may be caused by inactivation of Ptc1 or Sufu?

Answer 15

Inactivates tumour suppressors

Question 16

What effect does activation of Smo have in relation to causing cancer?

Answer 16

Upregulates protooncogenes

Question 17

What is a treatment for certain cancers that effects the Hh signalling pathway. What are the disadvantages of this treatment?

Answer 17

Smo inhibitors. Work in the short term but tumour cells acquire resistant via a mutation in Smo