Trends in Cell Biology
ReviewLeukocytes navigate by compass: roles of PI3Kγ and its lipid products
Section snippets
Chemotactic signals regulate Rho GTPases and PI3Ks
In neutrophils, chemoattractants stimulate G-protein-coupled receptors (GPCRs), which in turn activate a trimeric G protein, Gi, releasing the Gi βγ heterodimer from inhibition by αi (Fig. 2a). Gβγ regulates most of the known pathways activated by chemoattractants in leukocytes. Experimental manipulations that inactivate Gβγ6 or inhibit activities of several downstream effectors of Gβγ impair leukocyte motility in response to chemoattractants (Fig. 2a); these effectors include: PI3Ks7., 8.,
PI3K lipid products: indicators of signalling polarity in motile cells
Both neutrophils and Dictyostelium amoebas can create gradients of PI3K-generated signals across their surfaces that are steeper than the extracellular gradient of chemoattractant and that closely parallel cell polarity and accumulation of F-actin. The steep intracellular gradients were detected in experiments that used recombinant green-fluorescent protein (GFP)-tagged pleckstrin homology (PH) domains – small modules of ∼120 amino acids that associate with specific membrane-bound phospholipids
The PI3Kγ isozyme is key – but not the whole story
Three laboratories recently reported36., 37., 38. that genetic disruption of the PI3Kγ isozyme produces mice with neutrophils that show defective migration responses to chemoattractant in vitro and impaired accumulation at sites of inflammation in vivo. PI3Kγ-deficient mouse neutrophils produced little or no PtdIns(3,4,5)P3 after stimulation with chemoattractants such as the tripeptide formyl-Met-Leu-Phe (fMLP), interleukin 8, or complement factor 5a36., 37., 38.. These neutrophils showed
Roles for PI3K lipid products in cell polarity and pointing the compass
Lipid products of PI3Kγ emerge as strong candidates for a role intimately related to the cellular compass that directs chemotaxis, based on several lines of evidence: the motility defect of PI3Kγ-deficient neutrophils36., 37., 38., the PI3K requirement for chemoattractant-induced activation of Rho GTPases19., 20. and observations that PI3K lipid products accumulate at the leading edge of migrating cells (Fig. 3)28., 29., 30.. As compass molecules, lipid products of PI3Kγ would organize the
Positive feedback might not suffice to establish polarity
It is unlikely that localized positive feedback by itself accounts for the extreme difference in concentrations of PI3K lipid products at the leading versus the trailing edges of chemotaxing leukocytes. An attractive model (Fig. 5b) to explain creation of steep signalling gradients incorporates, in addition to localized enhancement of the extracellular signal (positive feedback), a rapidly diffusible global inhibitor of the signal29., 53.. According to this notion, upon exposure to a
Full steam ahead
Taken together, a body of observations and experiments strongly suggests that lipid products of PI3Ks play significant roles as compass molecules in neutrophil polarity and chemotaxis. Many questions remain to be explored. First, and probably most important, experiments must be designed to ask whether local accumulation of PI3K lipid products at the plasma membrane is necessary or sufficient to dictate the spatially specific activation of key Rho GTPases and consequently cell polarity.
Other
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- 1
P.R. is currently at: Incyte Genomics, 3160 Porter Drive, Palo Alto, CA 94304, USA.
- 2
G.S. is currently at: Senomyx, Inc., 11099 N. Torrey Pines Drive, Suite 160, La Jolla, CA 92037, USA.