Research highlight

Redistributing Ras

Nature Chemical Biology

April 26, 2010

A small molecule inhibitor reveals a new enzyme that regulates the location and activity of Ras, a signaling protein that is often mutated in cancer cells. These results, as reported this week in Nature Chemical Biology, provide important new insights into the Ras signaling pathway and suggest a possible cancer therapeutic strategy.

The cellular location of Ras is known to be regulated by reversible attachment and removal of the fatty acid, palmitic acid, to a cysteine in the protein. This dynamic control of location, in turn, regulates Ras signaling activity. Previously, the enzyme responsible for Ras depalmitoylation ― the removal of palmitic acid ― was not known.

By developing a potent and specific inhibitor for APT1 Herbert Waldmann, Philippe Bastiaens and colleagues were able to demonstrate that this enzyme depalmitoylates Ras in cells. Inhibiting ATP1 led to the broad redistribution of Ras and as a result reduced Ras signaling. The scientists further found that in cells expressing a constitutively-active, oncongenic Ras mutant, inhibiting APT1 caused a partial reversion from cancerous to a non-cancerous phenotype.

doi: 10.1038/nchembio.362

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