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Science 26 April 1991:
Vol. 252. no. 5005, pp. 576 - 579
DOI: 10.1126/science.1902323
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Articles

Science, Vol 252, Issue 5005, 576-579
Copyright © 1991 by American Association for the Advancement of Science

articles

Regulation of Ras-GAP and the neurofibromatosis-1 gene product by eicosanoids

JW Han, F McCormick, and IG Macara

Department of Biophysics, University of Rochester Medical Center, NY 14642.

Ras-GAP (GTPase activating protein) is a regulatory protein that stimulates the intrinsic guanosine triphosphatase (GTPase) activity of the proto-oncogene product p21ras. A domain of the neurofibromatosis gene product (NF1) that has sequence similarity to the catalytic domain of Ras-GAP and to yeast IRA gene products also has a specific stimulatory activity toward p21ras GTPase. Arachidonic acid and phosphatidic acid inactivate GAP, but no agents have been identified that stimulate GAP and thereby switch p21ras off. With the use of recombinant Ha-c-Ras and Ras-GAP, NF1, and GAP catalytic domains, it was found that prostaglandins PGF2 alpha and PGA2 stimulated Ras-GAP and that prostacyclin PGI2 inhibited Ras-GAP. The stimulatory effect of PGF2 alpha was saturable and structure-specific and competed with the inhibitory effect of arachidonic acid. Arachidonic acid also inhibited the catalytic activity of NF1, but prostaglandins were not stimulatory. These results suggest a mechanism for the allosteric control of Ras function through the modulation of arachidonate metabolism.


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