Biomedical Engineering Reference
In-Depth Information
ics of feedback loops in the EGFR network. And finally, we conclude by de-
scribing some of the current challenges involved in modeling EGFR at the tissue
level.
2.
TWO EXAMPLES OF EGFR SIGNALING IN
FRUIT FLY DEVELOPMENT
EGFR is recurrently used in fruit fly development (see Shilo (7) for a recent
review). The pleiotropic nature of EGFR signaling was realized when mutations
affecting different stages of development were mapped to the same location, the
Egfr
gene.
1
Within several years, the
Drosophila
EGFR ligands, all secreted
molecules, were identified: Gurken, Spitz, and Keren, all three being homolo-
gous to the human Transforming Growth Factor alpha (TGF
); and Vein, a
homologue of the human Neuregulin. Several inhibitors have also been identi-
fied. Most relevant to our discussion here is Argos, a secreted inhibitor acting
through sequestering the activating ligands (9). At this time, no mammalian
counterpart of Argos has been identified.
The presence of multiple ligands and inhibitors of EGFR signaling does not
necessarily imply redundancy in the system. Gurken, Spitz, and Keren are pro-
duced as transmembrane precursors and activated through a proteolytic cleav-
age. In contrast, Vein and Argos are expressed in their active secreted forms.
Furthermore, Spitz, Vein, and Argos, when acting in a feedback fashion, require
a different threshold of signaling activity for their induction. The different
modes of induction reflect the different modules of regulations used to limit the
availability of the molecules. The different regulations are translated into differ-
ent characteristics of the molecules (e.g., time delay upon induction, steep ver-
sus gradual response to induction) that may govern the choice of using a specific
ligand/inhibitor at a given place and time. And finally, the molecules have dif-
ferent transport and kinetic properties (e.g., diffusion coefficient, binding rate
constants) that would influence the way they regulate EGFR activity.
In the following two sections, we review two well-studied examples of
EGFR-mediated tissue patterning during the egg and embryonic development in
the fruit fly
Drosophila melanogaster
. During embryogenesis, an initial gradient
of EGFR activity created by a locally secreted activator is fine-tuned by a se-
creted inhibitor (10,13,14). Spitz acts as the activator that induces the expression
of Argos in a feedback fashion. During egg development, the initial domain of
EGFR activity is first expanded by a secreted activator and later refined by a
secreted inhibitor (11). In this case, Gurken acts as the initial activator that in-
duces the expression of Spitz and subsequently Argos. Thus, Gurken, Spitz, and
Argos define a spatially distributed network controlling the EGFR activation.
These two examples illustrate the patterning versatility of the autocrine and
paracrine EGFR networks.
