Editors' ChoiceCell Motility

Shifting into Reverse

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Science's STKE  29 May 2007:
Vol. 2007, Issue 388, pp. tw187
DOI: 10.1126/stke.3882007tw187

Dictyostelium discoideum are a widely used model system for the study of cellular motility. Like many mammalian cells, this single-celled organism exhibits both chemoattractive and chemorepulsive responses. It is well understood that chemoattraction involves polarization of membrane lipids with phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) accumulating at the front of the cell, which is oriented toward the area with higher concentration of chemoattractant, and the lipid phosphatase PTEN at the back of the cell, where lower concentration of the attractant is present; however, the mechanisms that control chemorepulsion are less well understood. Keizer-Gunnink et al. used analogs of cAMP, such as 8CPT-cAMP, to stimulate chemorepulsion of D. discoideum and monitored the accumulation of PIP3, phosphatidylinositol 3-kinase (PI3K), and PTEN by immunofluorescence techniques. In the presence of the chemorepulsive gradient, PIP3 and PI3K were enriched at the front of the cells (where concentrations of the repellent were lower), whereas PTEN was enriched at the back of the cell (where the repellent concentration was higher). Thus, the polarity of the cells with respect to the chemorepulsive gradient was opposite that of cells in a chemoattractive gradient. Cells in which two of three genes encoding PI3K or the gene encoding phospholipase C (PLC) were knocked out showed a chemoattractant response to cAMP but no response to the chemorepulsive 8CPT-cAMP. Exposure of the cells to cAMP stimulates PLC activity, which metabolizes phosphatidylinositol-(4,5)-diphosphate (PIP2) to produce diacylglycerol and inositol trisphosphate, whereas 8CPT-cAMP leads to inhibition of PLC activity. Thus, in a chemoattractive gradient, the combination of PI3K and PLC activity at the front of the cell leads to a loss of PIP2 to which PTEN binds, thereby causing PTEN to accumulate in the rear of the cell and PIP3 to accumulate at the front of the cell. The authors propose that in a chemorepulsive gradient, PLC activity is inhibited, which allows PIP2 to remain high in the side of the cell where the repellent concentration is highest, thereby recruiting PTEN to this side of the cell and allowing the cell to polarize PIP3 in a direction away from the highest concentrations of repellent and thus move away. In the life of D. discoideum, both chemorepulsion and chemoattraction are involved in the response to starvation with a switch from a repulsive to an attractive behavior. After a short period of starvation (~1 hour), the cells migrate away from each other, and during this time they have the G protein that inhibits PLC. After longer periods of starvation (~5 hours), the cells secrete cAMP and produce the G protein that stimulates PLC, thereby allowing the cells to coalesce and form a multicellular structure

I. Keizer-Gunnink, A. Kortholt, P. J. M. Van Haastert, Chemoattractants and chemorepellents act by inducing opposite polarity in phospholipase C and PI3-kinase signaling. J. Cell Biol. 177, 579-585 (2007). [Abstract] [Full Text]

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