In an exemplary illustration of the collaborative spirit of the Department of Integrative Biology and Pharmacology, the laboratories of Dr. Levental, Dr. Hancock, and Drs. Dial and Lichtenberger have combined forces for a recent publication showing interesting effects of bile acids on plasma membrane lateral organization. The collaboration was kindled by Drs. Lichtenberger’s and Dial’s previous work showing that unconjugated bile acids were both cytotoxic and disruptive of synthetic model membranes. Dr. Leventals favorite model system –the Giant Plasma Membrane Vesicles–represented the ideal extension of this work, filling the gap between the relatively complex cellular systems and the fully synthetic, but experimental tractable, model membranes. As expected, cytotoxic concentrations of bile acids dissolved isolated plasma membranes, definitively validating Dr Lichtenberger’s long – standing hypothesis that the mechanism of bile acid – induced cell damage is plasmalemmal disruption.
However, a wholly unexpected effect occurred at much smaller bile acid concentrations… both common unconjugated bile acids (cholic and deoxycholic) dramatically increased the stability of lipid raft domains in isolated plasma membranes. With colleagues from Dresden, Germany, Dr. Levental characterized this effect and found it to be dependent on specific intercalation of the bile components into non-raft domains.
A (metaphorical) high-energy hallway collision between Dr Yong Zhou (the primary and co-corresponding author) and Drs Levental and Lichtenberger led to a discussion that illuminated the in vivo relevance of these observations. Independently, Dr. Zhou (with CRB graduate students Kelsey Maxwell and Mariya Lu) had been characterizing the effects of bile acids on Ras nanoclustering in intact cell membranes and finding specific effects on the organization and signaling of the K-Ras isoform. The missing piece of the puzzle was the demonstration that bile acids had the capability of potentiating growth factor-induced oncogenic signaling through K-Ras, weaving a narrative thread from synthetic lipid membranes through to cancer.
This work was accepted for publication in the Journal of Biological Chemistry and selected for the cover of the Dec. 13th issue. Congratulations to all involved and thanks to the wonderful colleagues in IBP for fostering the collegial spirit of that makes such fruitful collaborations possible.
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