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Principles of Cell Signaling and Biological Consequences

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Student #14 Response

20 May 2005

14 14

In this paper, the authors elucidate the previously unknown nature of the crosstalk between the EGFR and Notch pathways in Drosophila. In their model, the Gro protein sits at the junction of the EGFR and Notch. They demonstrate that increased phosphorylation of Gro by MAPK causes a decrease in Gro-mediated repression of Notch cascade proteins, and therefore an increase in Notch-mediated transcription. The phenotypic effect is that expression of a Gro mutant which cannot be phosphorylated by MAPK causes a decrease in wing veins, while the expression of a constitutively phosphorylated Gro mutant causes an increase in wing veins. Similar observations were noted in bristle development. The combination of in-vitro and in-vivo data makes a strong case that the Gro proteins serves as the junction between the EGFR and Notch pathways.

I agree with Student 4's assesement that this paper gives strong biochemical, functional and phenotypic evidence of the crosstalk between the Notch and EGFR pathways via the Gro protein. The paper is well- written and convicing, although to a non-Drosophilist audience it may have been helpful to have some additional explanation of the physiological reason for why EGFR would need to silence the Notch pathway. My only other concern is that the authors' biochemical examination of MAPK activation is not entirely complete. In Figure 1, the authors used the Drosophila SL2 cell line for their experiments, which has increased levels of Ras and Raf, components of the MAPK pathway. (1) Consistenly with this, in Figure 1c and 1f there is some phosphorylation of Gro in unstimulated cells. The authors claim that this is likely due to baseline MAPK activity, but this notion would be better supported if they showed the increased phosphorylation of Ras following transfection, along with baseline levels of Ras activity as a negative control.

Reference:

Kimchie Z, Segev O, Lev Z. Maternal and embryonic transcripts of Drosophila proto-oncogenes are expressed in Schneider 2 culture cells but not in l(2)gl transformed neuroblasts. Cell Differ Dev. 1989 Mar;26 [PubMed]

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