Differing Src signaling levels have distinct outcomes in Drosophila.
High levels of Src activity are found in a broad spectrum of cancers. The roles of Src and its negative regulator Csk have been extensively studied, although results have often proved contradictory or the relevance to whole organisms is unclear. In Drosophila, overexpression of either Src orthologue resulted in apoptotic cell death, but paradoxically, reducing dCsk activity led to over-proliferation and tissue overgrowth. Here, we show that in Drosophila epithelia in situ, the levels of Src signaling determine the cellular outcome of Src activation. Apoptotic cell death was triggered specifically at high Src signaling levels; lower levels directed antiapoptotic signals while promoting proliferation. Furthermore, our data indicate that expression of kinase-dead Src isoforms do not necessarily act as dominant-negative factors, but can instead increase Src pathway activity, most likely by titrating Csk activity away from endogenous Src. The importance of Src activity levels was emphasized when we examined oncogenic cooperation between Src and Ras: malignant overgrowth was observed specifically when high Src signaling levels were achieved. We propose a model in which low levels of Src signaling promote survival and proliferation during early stages of tumorigenesis, whereas strong Src signaling, coupled with antiapoptotic signals, directs invasive migration and metastasis during advanced tumor stages.
Vidal
Marcos
M
Brookdale Department of Molecular, Cell, and Developmental Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Warner
Stephen
S
Read
Renee
R
Cagan
Ross L
RL
D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D004330:Drosophila / Q000201:enzymology*; D011905:Genes, ras; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000209:etiology* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D019061:src-Family Kinases / Q000502:physiology*
C086603:Matk protein, mouse; D011505:Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases