Biomedical Engineering Reference
In-Depth Information
Figure 7
. (
A
) A tentative structure of a positive feedback loop in the Rhomboid/Spitz system. Ligand
binding stimulates ligand release. Receptor activation leads to activation of the canonical Ras/MAPK
signal transduction pathway. The MAPK activity leads to degradation of CF
2
, a transcription factor
that inhibits transcription of the ligand-releasing protease,
rhomboid
(
rho
). In the absence of CF
2
inhi-
bition,
rhomboid
is synthesized. The mature Rhomboid (Rho) protein cleaves the transmembrane Spitz
(mSpitz) in the Golgi into its secreted form (PM = plasma membrane). (
B
) The steady-state ligand
field due to a single ligand-releasing cell. Parameters:
h
= 0.5
m,
k
e
= 0.1 min
-1
,
k
off
= 0.1 min
-1
,
R
cell
=
1 x 10
4
receptors/cell surface,
D
= 1 x 10
-7
cm
2
/s,
k
on
= 0.1 Nm
-1
min
-1
, maximal rate of ligand release
Q
s
= 100 molecules/cell-min, cell area = 25
m
2
. (
C
) A small cluster of cells with constitutively active
Rhomboid expression can generate an expanding wave of Rhomboid induction. The critical value of
ligand release necessary to generate the wave is plotted as a function of the number of cells within the
cluster (
N
). The generation function for Rhomboid was approximated by a Heaviside function, such
that Rhomboid expression can be only in two states, "on" and "off." See Pribyl et al. (25) for the de-
tailed definition of model parameters and its computational analysis.
3.2. Positive Feedback by Rhomboid and Spitz
The Rhomboid/Spitz module amplifies the oocyte-derived Gurken signal in
eggshell patterning (11,45,46). In the emerging picture, EGFR-activated
Ras/MAPK pathway relieves the transcriptional repression of
rhomboid
(47,48).
Rhomboid then stimulates the secretion of Spitz that binds to EGFR on the
ligand-producing cells and their neighbors (Figure 7A). This information about
signaling in a single cell can be combined with the transport model from the