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Biophys J, January 2002, p. 50-63, Vol. 82, No. 1
*Divisions of Biology, California Institute of Technology,
Pasadena, California 91125 and Department of Electrical
and Computer Engineering, Johns Hopkins University, 105 Barton Hall,
Baltimore, Maryland 21218 USA
Eukaryotic cells can detect shallow gradients of
chemoattractants with exquisite precision and respond quickly to
changes in the gradient steepness and direction. Here, we describe a
set of models explaining both adaptation to uniform increases in
chemoattractant and persistent signaling in response to gradients. We
demonstrate that one of these models can be mapped directly onto the
biochemical signal-transduction pathways underlying gradient sensing in
amoebae and neutrophils. According to this scheme, a locally acting
activator (PI3-kinase) and a globally acting inactivator (PTEN or a
similar phosphatase) are coordinately controlled by the G-protein
activation. This signaling system adapts perfectly to spatially
homogeneous changes in the chemoattractant. In chemoattractant
gradients, an imbalance between the action of the activator and the
inactivator results in a spatially oriented persistent signaling,
amplified by a substrate supply-based positive feedback acting through
small G-proteins. The amplification is activated only in a continuous presence of the external signal gradient, thus providing the mechanism for sensitivity to gradient alterations. Finally, based on this mapping, we make predictions concerning the dynamics of signaling. We
propose that the underlying principles of perfect adaptation and
substrate supply-based positive feedback will be found in the sensory
systems of other chemotactic cell types.
Biophys J, January 2002, p. 50-63, Vol. 82, No. 1
© 2002 by the Biophysical Society 0006-3495/02/01/50/14 $2.00
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