Biomedical Engineering Reference
In-Depth Information
of the mechanism that mediates the formation of a highly polarized distribution
of actin polymers in response to a relatively mild chemoattractant gradient.
The chemoattractant gradient is transmitted to the actin polymerization ma-
chinery by a signal transduction pathway that starts with receptors on the cell
surface and terminates in proteins that catalyze actin polymerization. It is there-
fore conceivable that actin polymers inherit their polarized distribution from
some molecule that is upstream of the polymers in the pathway. Recent experi-
ments have shown that certain membrane-resident phosphoinositides—namely,
phosphatidylinositol 3,4,5-phosphate (PIP
3
)
1
and phosphatidylinositol 4,5-
phosphate (PIP
2
)—are among the earliest polarized components of the pathway.
Moreover, these phosphoinositides activate the enzymes that catalyze actin po-
lymerization, thus generating the force that pushes the membrane forward. In
other words, the morphological polarity corresponding to the extension of a pro-
trusion is driven by the chemical polarity corresponding to the phosphoinositide
localization. Thus, the key question in the study of gradient sensing becomes:
What is the mechanism of phosphoinositide localization?
Our attempts to address this question exemplify the modeling methodology
enunciated in this volume (see Part II, chapter 2, by Socolar). We observed that
the seemingly complex patterns of phosphoinositide localization were strongly
reminiscent of the spatiotemporal dynamics associated with the activator-
inhibitor class of models. Encouraged by this analogy, we screened the phospho-
inositide signaling pathways for activators and inhibitors, and selected the pair
that seemed most consistent with the prevailing experimental literature. We then
formulated and simulated an activator-inhibitor model in which membrane-
resident phosphoinositides and cytosolic inositol phosphates played the roles of
activator and inhibitor, respectively. As we show in §2, the simulations are in
remarkable agreement with all the spatiotemporal dynamics observed in the lit-
erature. These findings strongly suggest that the dynamics of the gradient sens-
ing mechanism are consistent with the activator-inhibitor class of models.
However, there are several hypotheses in the literature regarding the molecular
identity of the activator and the inhibitor. These open questions, which can only
be resolved by experiments, are discussed in §3.
We begin by giving a brief description of the phosphoinositide signaling
pathways and the spatiotemporal dynamics of the phosphoinositide localization.
1.1. Signaling Pathways
The signaling steps that follow receptor activation are the subjects of ongo-
ing research. The model systems studied most intensively are
Dictyostelium dis-
coideum
and neutrophils. In these systems, receptor-ligand binding activates
heterotrimeric G-proteins, which stimulate PI3K, the enzyme that catalyzes
the synthesis of PIP
3
(Figure 2a). In neutrophils, it has been shown that PIP
3
