In Drosophila, clones or restricted sets of cells expressing the Ras85DV12 activated RAS mutation result in overproliferation, but typically do not produce neoplastic or metastatic phenotypes (see FBhh0000474). Multiple genes involved in regulation of actin dynamics were tested in combination with Ras85DV12, screening for exacerbation of the overproliferation phenotype.
The effects of combining overexpression of pico (ortholog of human RAPH1, aka Lamellipodin or LPD) with activated Ras85D (and with expression of a GFP label) were assessed in larval imaginal discs and optic lobes of the larval brain. Significant tissue overgrowth was observed and shown to be made up of GFP-positive cells; redistribution of cells to more distant sites was also observed, including from the brain to the ventral nerve cord. Invasive behavior was shown to be dependent upon JNK signaling. In the brain, it was shown that these effects are glial-specific and require glial co-expression of Ras85DV12 and pico.
Overexpression of the Drosophila gene that encodes profilin (chic), when assessed in these assays, results in similar phenotypes. For chic, also, the tumorigenic phenotypes require glial expression of both Ras85DV12 and chic. A loss-of-function allele of chic, when expressed in cells in addition to co-expression of Ras85DV12 and pico, reduces the level of invasive phenotypes.
[updated Nov. 2019 by FlyBase; FBrf0222196]
RAPH1 encodes a protein that belongs to the Mig10/Rap1-interacting adaptor molecule/Lamellipodin (MRL) family of adapter proteins, which function in cell migration. Members of this family contain pleckstrin-homology domains, Ras-association domains, and proline-rich C-termini. The protein encoded by this gene regulates actin dynamics through interaction with Ena/Vasodilator proteins as well as direct binding to filamentous actin to regulate actin network assembly. [Gene Cards, RAPH1; 2019.11.12]
Profilins are small actin-binding proteins found in eukaryotes and certain viruses that are involved in cell development, cytokinesis, membrane trafficking, and cell motility. Profilin is involved in actin polymerization dynamics and also interacts with polyphosphoinositides (PPI) and proline-rich domains containing proteins. Through its interaction with PPIs, profilin has been linked to signaling pathways between the cell membrane and the cytoskeleton, while its role in membrane trafficking has been associated with its interaction with proline-rich domain-containing proteins (Krishnan and Moens, 2009; pubmed:28509986).
High-scoring ortholog of human genes KRAS, HRAS, and NRAS (many to many; multiple paralogs and orthologs in both species). Dmel\Ras85D shares 78-86% identity and 86-92% similarity with KRAS, HRAS, and NRAS; for these three human genes, Ras85D is the highest-scoring ortholog in Drosophila.
High-scoring ortholog of human RAPH1 (1 Drosophila to many human). Dmel\pico shares 26% identity and 39% similarity with human RAPH1.
High-scoring ortholog of human PFN4 (1 Drosophila to 4 human). Dmel\chic shares 28% identity and 42% similarity with human PFN4.