PDGF/VEGF signaling controls cell size in Drosophila.
BACKGROUND
In multicellular animals, cell size is controlled by a limited set of conserved intracellular signaling pathways, which when deregulated contribute to tumorigenesis by enabling cells to grow outside their usual niche. To delineate the pathways controlling this process, we screened a genome-scale, image-based Drosophila RNA interference dataset for double-stranded RNAs that reduce the average size of adherent S2R+ cells.


RESULTS
Automated analysis of images from this RNA interference screen identified the receptor tyrosine kinase Pvr, Ras pathway components and several novel genes as regulators of cell size. Significantly, Pvr/Ras signaling also affected the size of other Drosophila cell lines and of larval hemocytes. A detailed genetic analysis of this growth signaling pathway revealed a role for redundant secreted ligands, Pvf2 and Pvf3, in the establishment of an autocrine growth signaling loop. Downstream of Ras1, growth signaling was found to depend on parallel mitogen-activated protein kinase (MAPK) and phospho-inositide-3-kinase (PI3K) signaling modules, as well as the Tor pathway.


CONCLUSIONS
This automated genome-wide screen identifies autocrine Pvf/Pvr signaling, upstream of Ras, MAPK and PI3K, as rate-limiting for the growth of immortalized fly cells in culture. Since, Pvf2/3 and Pvr show mutually exclusive in vivo patterns of gene expression, these data suggest that co-expression of this receptor-ligand pair plays a key role in driving cell autonomous growth during the establishment of Drosophila cell lines, as has been suggested to occur during tumor development.
Sims
David
D
Morphogenesis Group, Ludwig Institute for Cancer Research (UCL Branch), Riding House Street, London, W1W 7BS, UK.
Duchek
Peter
P
Baum
Buzz
B
D000818:Animals; D019898:Autocrine Communication; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects; D004330:Drosophila / Q000166:cytology / Q000378:metabolism; D029721:Drosophila Proteins; D004527:Egg Proteins; D023281:Genomics / Q000379:methods; D009369:Neoplasms / Q000209:etiology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism* / Q000502:physiology; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases; D015398:Signal Transduction; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism* / Q000502:physiology
D029721:Drosophila Proteins; D004527:Egg Proteins; D010982:Platelet-Derived Growth Factor; C438367:Pvf1 protein, Drosophila; D012330:RNA, Double-Stranded; D042442:Vascular Endothelial Growth Factors; C438368:Pvr protein, Drosophila; D020794:Receptor Protein-Tyrosine Kinases