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J. Biol. Chem., Vol. 281, Issue 47, 36132-36139, November 24, 2006

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The Exchange Factor and Diacylglycerol Receptor RasGRP3 Interacts with Dynein Light Chain 1 through Its C-terminal Domain^*

From the Natural Products and Cancer Biology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii 96813

RasGRP3 is an exchange factor for Ras-like small GTPases that is activated in response to the second messenger diacylglycerol. As with other diacylglycerol receptors, RasGRP3 is redistributed upon diacylglycerol or phorbol ester binding. Several factors are important in determining the pattern of translocation, including the potency of the diacylglycerol analog, the affinity of the receptor for phospholipids, and in some cases, protein-protein interactions. However, little is known about the mechanisms that play a role in RasGRP3 redistribution aside from the nature of the ligand. To discover potential protein binding partners for RasGRP3, we screened a human brain cDNA library using a yeast two-hybrid approach. We identified dynein light chain 1 as a novel RasGRP3-interacting protein. The interaction was confirmed both in vitro and in vivo and required the C-terminal domain encompassing the last 127 amino acids of RasGRP3. A truncated mutant form of RasGRP3 that lacked this C-terminal domain was unable to interact with dynein light chain 1 and displayed a dramatically altered subcellular localization, with a strong reticular distribution and perinuclear and nuclear localization. These findings suggest that dynein light chain 1 represents a novel anchoring protein for RasGRP3 that may regulate subcellular localization of the exchange factor and, as such, may participate in the signaling mediated by diacylglycerol through RasGRP3.

Received for publication, May 30, 2006 , and in revised form, August 29, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Cancer Research Center of Hawaii, 651 Ilalo St., Suite 222-K, Honolulu, HI 96813. Tel.: 808-586-5868; Fax: 808-587-0742; E-mail: plorenzo{at}crch.hawaii.edu.

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