Question

can you answer questions 6,7, and 9?

Cell Signaling Pathways - A Case Study Approach L. Emtage, L. Bradbury, N. Coleman, D. Davenport, A. Dunning and I Grew Assignment: The Wnt/ b-catenin pathway zd Plasma membrane Ubiquitin-mediated degradation pratenin B-catenin B-catenin TCF MIDI Note: GSK3, APC and Axin together are called the B-catenin Destruction Complex. DSH is the abbreviation for Dishevelled. The human genome encodes many Fzd receptors, several Dsh proteins, one GSK3, and one ß-catenin.

Answer 1

ANSWERS:

5)

The ultimate outcome of the WNT-Frizzled receptor signalling pathway is to activate the Beta catenin transcription factor, leading to transcription of the target genes (beta catenin target genes).

6)

1. The degradation of beta catenin through ubiquitin mediated proteosomal method is a negative regulation found in this pathway. In the absence of a cognate WNT ligand on the frizzled receptor, beta catenin ( transcription factor) is excluded from the nucleus by its proteosomal degradtion. GSK 3 beta ubiquitinates beta catenin for proteosomal degradation.

2. The opposite effect upon ligand binding, is also the vice versa negative regulation , i.e GSK3 beta - DSH and APC binding to the receptor (Frizzled). This is the negative regulation of the ubiquitination process on beta catenin. This leads to accumulation of beta catenin in the cytoplasm, which then translocates to the nucleus and carries out transcription.

Biological signal transduction pathways can be understood by such antagonistic / agonistic effects on/by each signalling molecules.

7. LOSS OF FUNCTION EFFECTS:

-- FZD receptor -- This would lead to constitutive degradation of the beta catenin transcription factor, and hence the signalling pathway is OFF ( No transcription of beta catenin target genes)

-- DSH(Dishevelled) : This again would have the aforementioned effect - Loss of its activity would not effectively let APC and GSK3 beta bind to the frizzled receptor-- And hence beta catenin would be constitutively degraded.

--GSK3 BETA: Interestingly, loss of GSK3 beta could in theory (atleast) lead to constitutive activation of the beta catenin transcription factor. As the main protein of the beta catenin destruction complex, loss of function of GSK3 beta could relieve Beta catenin (transcription factor) from proteosomal degradation , hence activate transcription.

--Beta Catenin: Loss of function in beta catenin would keep the WNT - FZD signalling pathway OFF ( i.e No beta catenin target gene transcription ) both in the presence or absence of WNT ligand -- As beta catenin is the terminal transcription factor target of the entire pathway.

8. NOTUM:

Notum supposedly acts as a extracellular negative feedback regulator of the WNT ligand itself. Notum could restrain excessive activation of the WNT - Beta catenin pathway.

9. As it is clear from the information that WNT acts extracellularly and binds to Frizzled receptor on the plasma membrane ( Hydrophobic in nature), it should be that WNT protein is attached with hydrophobic/lipid moieties prior to its secretion from a signalling cell,