THE P-REX2 AND FLII SIGNALLING AXIS IN MELANOMA

Abstract

RAC1 GEFs have been shown to be capable of determining the signalling outputs of RAC1 signalling, specifically P-REX1 has been shown to interact with and facilitate RAC1 signalling through FLII. P-REX1 is capable of enhancing cell migration and this is dependent on FLII and the downstream phosphorylation of MLC2 enhancing cell contractility. P-REX1 shows limited mutations in melanoma, in contrast P-REX2 is highly mutated and thus may have greater clinical significance. Limited data in the literature shows that SNPs and truncations within P-REX2 appear to escape PTEN regulation and assist in oncogenic transformation. Less is known about how P-REX2 may direct RAC1 signalling. I sought to investigate the role of P-REX2 and its truncations in melanoma initiation and progression. Given the known interaction between P-REX1 and FLII, I sought to determine if this interaction persists with the P-REX1 paralogue P-REX2 and elucidate any potentially oncogenic implications. I demonstrate, through over expression studies and within the endogenous oncogenic setting, that PREX-2 interacts with FLII, which has not yet been reported in the current literature. Furthermore, truncations of P-REX2 not only maintain the ability to interact with FLII but also have a greater capacity to induce oncogenic transformation, in comparison to full-length P-REX2. These interactions have multiple, quantifiable effects on the intracellular structure, migration and invasive capacity of melanocytes, ultimately leading to a highly oncogenic phenotype. This thesis presents novel research into the roles and interactions of PREX-2, an under-studied protein with a link to the formation of melanoma. Through detailed characterisation of the molecular interactions and the intracellular and in-vivo effects of PREX-2, the work presented here shines further light onto the molecular mechanisms that underly the formation and progression of melanoma.

Date of Award	1 Aug 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Adam Hurlstone (Supervisor), Angeliki Malliri (Supervisor) & Claudia Wellbrock (Supervisor)