Diacylglycerol Kinase {zeta} Regulates Ras Activation by a Novel Mechanism

doi:10.1083/jcb.152.6.1135

Published online 19 March 2001. doi:10.1083/jcb.152.6.1135

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© The Rockefeller University Press, 0021-9525/2001//1135 $5.00
The Journal of Cell Biology, Volume 152, Number 6, , 2001 1135-1144

Original Article

Diacylglycerol Kinase ${zeta}$ Regulates Ras Activation by a Novel Mechanism

Matthew K. Topham^a and Stephen M. Prescott^a

^a The Huntsman Cancer Institute and Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84112
The Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84132.(801) 585-6345(801) 585-3401

stephen.prescott{at}hci.utah.edu

Guanine nucleotide exchange factors (GEFs) activate Ras by facilitatingits GTP binding. Ras guanyl nucleotide-releasing protein (GRP)was recently identified as a Ras GEF that has a diacylglycerol(DAG)-binding C1 domain. Its exchange factor activity is regulatedby local availability of signaling DAG. DAG kinases (DGKs) metabolizeDAG by converting it to phosphatidic acid. Because they canattenuate local accumulation of signaling DAG, DGKs may regulateRasGRP activity and, consequently, activation of Ras. DGK ${zeta}$ , butnot other DGKs, completely eliminated Ras activation inducedby RasGRP, and DGK activity was required for this mechanism.DGK ${zeta}$ also coimmunoprecipitated and colocalized with RasGRP, indicatingthat these proteins associate in a signaling complex. Coimmunoprecipitationof DGK ${zeta}$ and RasGRP was enhanced in the presence of phorbol esters,which are DAG analogues that cannot be metabolized by DGKs,suggesting that DAG signaling can induce their interaction.Finally, overexpression of kinase-dead DGK ${zeta}$ in Jurkat cells prolongedRas activation after ligation of the T cell receptor. Thus,we have identified a novel way to regulate Ras activation: throughDGK ${zeta}$ , which controls local accumulation of DAG that would otherwiseactivate RasGRP.

Key Words: diacylglycerols • diacylglycerol kinase • signal transduction • H-Ras oncogenes • RasGRP protein

Abbreviations used in this paper: CMV, cytomegalovirus; DGK,DAG kinase; GAP, GTPase-activating protein; GEF, guanine nucleotideexchange factor; GFP, green fluorescent protein; GRP, guanylnucleotide-releasing protein (GRP); HA, hemagglutinin; PA, phosphatidicacid; PMA, phorbol 12-myristate 13-acetate; TCR, T cell receptor.

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