title: MRL proteins cooperate with activated Ras in glia to drive distinct oncogenic outcomes.
abstract: The Mig10/RIAM/Lpd (MRL) adapter protein Lpd regulates actin dynamics through interactions with Scar/WAVE and Ena/VASP proteins to promote the formation of cellular protrusions and to stimulate invasive migration. However, the ability of MRL proteins to interact with multiple actin regulators and to promote serum response factor (SRF) signalling has raised the question of whether MRL proteins employ alternative downstream mechanisms to drive oncogenic processes in a context-dependent manner. Here, using a Drosophila model, we show that overexpression of either human Lpd or its Drosophila orthologue Pico can promote growth and invasion of RasV12-induced cell tumours in the brain. Notably, effects were restricted to two populations of Repo-positive glial cells: an invasive population, characterized by JNK-dependent elevation of Mmp1 expression, and a hyperproliferative population lacking elevated JNK signalling. JNK activation was not triggered by reactive immune cell signalling, implicating the involvement of an intrinsic stress response. The ability to promote dissemination of RasV12-induced tumours was shared by a subset of actin regulators, including, most prominently, Chicadee/Profilin, which directly interacts with Pico, and, Mal, a cofactor for serum response factor that responds to changes in G:F actin dynamics. Suppression of Mal activity partially abrogated the ability of pico to promote invasion of RasV12tumours. Furthermore, we found that larval glia are enriched for serum response factor expression, explaining the apparent sensitivity of glial cells to Pico/RasV12overexpression. Taken together, our findings indicate that MRL proteins cooperate with oncogenic Ras to promote formation of glial tumours, and that, in this context, Mal/serum response factor activation is rate-limiting for tumour dissemination.
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: E
authors.initials: E
authors.lastname: Taylor
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: N
authors.initials: N
authors.lastname: Alqadri
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.|Centre for Cell Imaging, Biosciences Building, University of Liverpool, Liverpool, UK.
authors.forename: L
authors.initials: L
authors.lastname: Dodgson
authors.affiliation: Centre for Cell Imaging, Biosciences Building, University of Liverpool, Liverpool, UK.
authors.forename: D
authors.initials: D
authors.lastname: Mason
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: E
authors.initials: E
authors.lastname: Lyulcheva
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: G
authors.initials: G
authors.lastname: Messina
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.|Centre for Cell Imaging, Biosciences Building, University of Liverpool, Liverpool, UK.
authors.forename: D
authors.initials: D
authors.lastname: Bennett
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D029721:Drosophila Proteins; D008565:Membrane Proteins; C533183:Pico protein, Drosophila; C493339:RAPH1 protein, human; D026362:Serum Response Factor; D018631:ras Proteins