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 RasV12 tumours. Furthermore, we found that larval glia are enriched for serum response factor expression, explaining the apparent sensitivity of glial cells to Pico/RasV12 overexpression. 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.

Rounding up the Usual Suspects: Assessing Yorkie, AP-1, and Stat Coactivation in Tumorigenesis

“…In ph tumors, co-expression of Bsk-DN reduces the volume of mutant clones [ 34 ]. Similarly, JNK activity is induced and co-expression of Bsk-DN can suppress tumorigenesis in Ras + Pico [ 96 ], Ras + Src [ 83 , 97 ], and activated N + Src [ 98 ] models. However, in some tumors, tumor growth and invasive potential can be uncoupled from each other.…”

Modelling Cooperative Tumorigenesis inDrosophila

“…Moreover, a genetic screen of the kinome led to the identification of RIOK1 and RIOK2 kinases, which promote mTORC-Akt signalling to drive glial tumour growth [ 113 ]. A recent study has also revealed cooperative tumorigenesis in glial tumour growth and invasion between Ras V12 and overexpression of pico (a MRL family gene), chickadee ( profilin, encoding an actin-cytoskeletal regulator) or Mal (encoding a cofactor of Serum Response Factor (SRF)) [ 107 ], suggesting that SRF signalling might be a novel pathway to investigate in human glioblastomas.…”

The True Story of Yeti, the “Abominable” Heterochromatic Gene of Drosophila melanogaster

“…Finally, YETI protein has also been implicated in cell cycle control in both mitosis and meiosis (Billmann et al, 2016). According with these results, it has been reported that Myc, a well-known oncogenic player (Bellosta et al, 2005; Jonchere et al, 2017; Taylor et al, 2017), and the DOMINO ATPase interact each other and are required for normal asymmetric neuroblast (NB) division. Live-imaging analysis of dom -or myc -depleted NBs showed that spindle morphology is affected resulting in aberrant divisions (Rust et al, 2018).…”