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Title: Role of VANGL1 as an effector of R-RAS
Author: Hartig, N.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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The WNT pathway plays a key role in development and disease. In addition to the better studied ß-catenin dependent pathway, WNT ligands can also activate the separate ‘non-canonical’ or Planar Cell Polarity (PCP) pathway. Perturbations in the PCP pathway contribute to the pathogenesis of a variety of diseases including cardiac and neural tube defects, and to the invasiveness of cancer cells. R-RAS subgroup GTPases share many of the properties of classical RAS GTPases including the ability to behave as oncogenes. However, they also have distinct functions of their own and how signalling and biological specificity is achieved is not fully understood. Using a proteomic approach to identify novel R-RAS subgroup effectors led to the identification of VANGL1, a WNT/PCP protein, demonstrated to be a novel R-RAS interacting protein. In this thesis, I have shown that VANGL1 functions as an effector of R-RAS and TC21. Using proteomic approaches, multiple VANGL1 interacting proteins have been identified and R-RAS, as well as selected Frizzled (FZD) receptors and the tyrosine kinase ROR2 can modulate at least some of these VANGL1 interactions. Furthermore, VANGL1 leads to the protein degradation of PRICKLE by a mechanism that remains to be determined, and R-RAS GTPases are able to inhibit this effect. Using RBD pulldown assays, I was able to show that WNT ligands and ROR2 can lead to the activation of R-RAS, and that R-RAS and TC21 are key mediators of RHO activation by WNT5a. Finally, I demonstrated that R-RAS/TC21 and VANGL1 are critically required for directed migration. The identification of R-RAS activation by WNT ligands and its interaction with VANGL1 provides an exciting new link between the R-RAS subgroup of the RAS family and the WNT/PCP pathway.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available