PATTERNING BY EGF RECEPTOR: MODELS FROM DROSOPHILA DEVELOPMENT - Complex Systems Science in Biomedicine - page 337

We hope that, in addition to being applicable to the mechanisms in Droso-
phila development, our models will be useful for the quantitative description of
EGFR signaling in higher organisms. Indeed, the molecular components and the
feedback loops in EGFR signaling are conserved across species. For example,
the positive feedback, similar to the one in the Rhomboid/Spitz system, was
identified in radiation responses of human autocrine carcinoma cells (54). There,
a pulse of ionizing radiation induces a primary wave of EGFR activation that
was then amplified by the positive feedback, which is based on the MAPK-
mediated TGF release and recapture by the cell. Central to this feedback is
activation of the ligand-releasing protease (TACE) that serves as the rate-
limiting component that controls ligand availability and, hence, receptor activa-
tion.
The negative feedback loop by Argos does not have a direct counterpart in
mammalian EGFR systems. The closest mode of regulation, discovered by Mai-
hle and colleagues (55), relies on a secreted form of EGFR. Secreted receptors
compete with the ones on the cell surface for the extracellular ligands, and in
this way control the level of cellular EGFR activation. This mode of regulation
has been described for both the ErbB1 and ErbB3 receptors, indicating that it is
a general mechanism in the ErbB receptor family. Several lines of evidence
from the same study support the physiological significance of this negative
mode of control. For example, the levels of secreted receptors can be used as
diagnostic markers in ovarian epithelial cancer (56). In the future, it will be im-
portant to investigate whether this mode of regulation also contributes in the
developmental context.

5.

ACKNOWLEDGMENTS

The authors are indebted to Trudi Schupbach and Lazaros Batsilas for their
critical reading of the manuscript. SYS thanks Sasha Berezhkovskii, Doug Lauf-
fenburger, Mark Lemmon, Cyrill Muratov, Gregory Reeves, Michal Pribyl, and
Steve Wiley for numerous helpful discussions. This work was supported by the
grants from the NSF and the Searle Foundation.

6.

NOTES

1. In accordance to the convention, the names of genes are italicized (i.e.,
gene ) while the names of proteins are written with the first letters capitalized
(i.e., Protein).
2. Vein has been shown to form a positive feedback loop during the pattern-
ing of ventral ectoderm (10). However, its contribution is redundant and only
important when the level of Spitz is reduced.