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Title: Molecular genetic analysis of the Drosophila MRL adapter protein in hyperplastic growth and experimental metastasis
Author: Alqadri, N. A.
ISNI:       0000 0004 6059 4859
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2016
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Members of the Mig-10/RIAM/Lamellipodin (MRL) family of adapter proteins transduce signals derived from growth factor receptors, via interactions with Ras GTPases and/or phospholipids, to changes in the actin cytoskeleton, increased cell motility, and altered cell adhesion properties. MRL proteins have roles in normal development and their overexpression is implicated in tumour development and cancer progression. The focus of this thesis has been to explore signalling upstream and downstream of the Drosophila MRL protein, encoded by pico, to better understand the effects of manipulating its function. This has been done both in the developing wing, where overexpressed pico is capable of driving hyperplastic overgrowth, and in the larval CNS, where pico cooperates with oncogenic Ras to promote both hyperproliferation and cell invasion. An important downstream consequence of pico overexpression is thought to be activation of the Serum Response Factor (SRF), which responds to changes in actin dynamics through the action of its cofactor Mal. An SRF-responsive reporter gene, whose expression recapitulates the distribution of SRF protein in the developing wing, has been used to provide the first in vivo evidence that pico, and its associated actin regulatory proteins, promote SRF signalling. This work has also helped to identify deterin, which encodes Drosophila Survivin, as an SRF target that is necessary for pico-mediated overgrowth of the wing by suppressing proliferation-associated cell death. SRF is also likely to be a key effector of pico in the brain, based on genetic evidence and the observation that cooperation between pico and oncogenic Ras is restricted to two populations of Repo-positive glial cells, which are enriched for SRF expression. This work has also explored the involvement of a potential cascade of protein phosphorylation upstream of pico using a panel of site-directed mutants in pico designed to abolish binding to specific MRL-associated proteins and/or mimic its phosphorylation state. Importantly, these findings are consistent with the known roles of MRL proteins in promoting growth via changes in the actin cytoskeleton, and support the potential involvement of MRL gain-of-function in tumour cell invasion and metastasis.
Supervisor: Bennett, D. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral