Biomedical Engineering Reference
In-Depth Information
2.2
SPATIOTEMPORAL DYNAMICS OF
EUKARYOTIC GRADIENT SENSING
K.K. Subramanian and Atul Narang
Department of Chemical Engineering,
University of Florida, Gainesville
The crawling movement of eukaryotic cells in response to a chemical gradient is a com-
plex process involving the orchestration of several subcellular activities. Although a
complete description of the mechanisms underlying cell movement remains elusive, the
very first step of
gradient sensing
, enabling the cell to perceive the imposed gradient, is
becoming more transparent. The increased understanding of this step has been driven by
the discovery that within 5-10 seconds of applying a weak chemoattractant gradient,
membrane phosphoinositides, such as PIP
3
, localize at the front end of the cell, where
they activate a process of intense actin polymerization and trigger the extension of a pro-
trusion. This train of events implies that the key to gradient sensing is a mechanistic un-
derstanding of the phosphoinositide localization. Since the phosphoinositide distribution
is highly localized compared to the shallow chemoattractant gradient, it has been sug-
gested that the cell merely amplifies the chemoattractant gradient. However, this cannot
be true since the phosphoinositide localization can display a bewildering array of spatial
distributions that bear no resemblance to the external chemoattractant profile. For in-
stance, a single phosphoinositide localization is produced in the face of multiple
chemoattractant sources. More surprisingly, the localization forms at a random location
even if the chemoattractant concentration is uniform. Here we show that all these seem-
ingly complex dynamics are consistent with the so-called activator-inhibitor class of
models. To this end, we formulate and simulate an activator-inhibitor model of gradient
sensing based on the phosphoinositide signaling pathways. Specifically, membrane-
resident phosphoinositides play the role of activator, and cytosolic inositol phosphates act
as inhibitor. The remarkable agreement between the simulated and observed dynamics of
phosphoinositide localization supports our conjecture that gradient sensing is a manifesta-
tion of an activator-inhibitor mechanism. However, the molecular identity of the activator
and inhibitor remains unresolved. We discuss several competing hypotheses in the litera-
ture regarding the identity of these molecules.
Address correspondence to: Atul Narang, Department of Chemical Engineering, University of Flor-
ida, Room 237 CHE, Gainesville, FL 32608 (ksubrama@che.ufl.edu).
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