Regulators of actin and cytoskeletal remodeling play a key role in orchestrating the cytoskeletal changes required for cell migration, in both normal and pathogenic contexts. Evidence is accumulating that, in addition to this function, actin remodeling regulators may participate in positive feedback networks that impact development of malignant phenotypes during the early stages of cellular transformation. Studies in Drosophila have contributed to understanding of these interactions.
Several slightly different models have been used; most use assays in wing discs with overexpression of Src64B or knockdown of Csk in discrete regions of the disc. Dmel\Src64B is the highest-scoring Drosophila ortholog of human gene SRC. Dmel\Csk is orthologous to the human CSK gene, a kinase that suppresses the activity of multiple genes, including the SRC proto-oncogene. Interacting genes were identified and characterized based on changes in the Src-related overproliferation phenotypes.
Actin modulators that have emerged as important in this process include ena (orthologous to human ENAH, EVL and VASP); tsr (orthologous to human CFL2, DSTN and CFL1); cpa (orthologous to human CAPZA1, CAPZA2 and CAPZA3); and cpb (orthologous to human CAPZB). A large-scale genetic screen has identified additional candidates.
The impact of overexpression of Dmel\ena has also been characterized in migrating embryonic macrophages (hemocytes) to address development of aggressive migratory behavior during cancer progression.
[updated Feb. 2021 by FlyBase; FBrf0222196]
Highest-scoring ortholog of human gene SRC (many to many; multiple paralogs and orthologs in both species). Dmel\Src64B shares 50% identity and 67% similarity with human SRC.
High-scoring ortholog of human CSK; moderate-scoring ortholog of human MATK (1 Drosophila to 2 human); Dmel\Csk shares 62% identity and 75% similarity with the human CSK gene.
Moderate-scoring ortholog of human ENAH, EVL and VASP.
Moderate-scoring ortholog of human CFL2, DSTN and CFL1.
High-scoring ortholog of human CAPZB.
Moderate- to high-scoring ortholog of human CAPZA1, CAPZA2 and CAPZA3.