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Genetic Analysis of Chemotaxis in Eucaryotic Cells Chemotaxis and phagocytosis are an
integral part of immune response and play a key role in wound healing, angiogenesis, and
embryogenesis. These fundamental cellular processes are found in all eukaryotes and have
remained essentially unchanged throughout evolution. Research in the last fifteen years in
D. discoideum showed that chemoattractants are sensed by the
same basic signal
transduction mechanisms as are many hormones,
neurotransmitters, odorants. The receptors for these cell-cell signaling molecules
activate heterotrimeric G-proteins that regulate phosphodiesterases,
phospholipases, ion
channels, and adenylyl cyclases. Our strategy is to exploit the
genetic
advantages of D. discoideum to discover mechanisms of sensing chemoattractant
gradients and to apply this information to higher eukaryotic cells. Consideration of the features of a chemotactic response presents
several fascinating and unique challenges.
Shallow external gradients must generate sharply localized internal
responses at the leading edges of the cells.
Moreover, cells at different points in the gradient sense equally
well so there is a powerful mechanism for background subtraction or
adaptation. We have suggested
that a balance between local excitatory and global inhibitory processes
controls the response to chemoattractants.
An extensive series of studies in the last several years have
indicated that the upstream components and reactions in the signaling
pathway are uniformly localized in cells exposed to a chemoattractant
gradient. However, downstream
responses such as PI (3,4,5)P3 accumulation and actin
polymerization are sharply localized towards the high side of the
gradient, suggesting that these responses are selectively activated at the
cell’s leading edge. We
have recently found that uniform stimuli transiently
recruit and activate
PI3Ks while PTEN is released from the plasma membrane.
Although chemoattractant receptors and G-proteins are evenly
distributed along the cell surface, gradients of chemoattractant cause
PI3Ks and PTEN to bind to the membrane at the front and the back of the
cell, respectively. This reciprocal regulation provides robust control of
PI(3,4,5)P3 and leads to its sharp accumulation at the
anterior. Interference with PI3Ks modifies chemotaxis while disruption
of PTEN broadens PI localization and actin polymerization in parallel.
Thus, counteracting signals from the upstream elements of the
pathway converge to regulate the key enzymes of PI metabolism, localize
these lipids, and direct pseudopod formation.
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This page was last edited 12/12/2003 |