Diacylglycerol kinase (DGK) plays an important role in phosphoinositide signaling cascade by regulating the intracellular level of diacylglycerol and phosphatidic acid. The DGK family is involved in various pathophysiological responses that are mediated through unique binding partners in different tissues and cells. In this study, we identified a small GTPase effector protein, IQGAP1, as a novel DGK zeta-associated complex protein. A bacterial endotoxin, lipopolysaccharide (LPS), facilitated the complex formation in macrophages. Both proteins co-localized at the edge and phagocytic cup of the cell. Furthermore, RNA interference-mediated knockdown of DGK zeta or IQGAP1 impaired LPS-induced Rac1 activation. Primary macrophages derived from DGK zeta(-/-) mice attenuated LPS-induced phagocytosis of bacteria. These results suggest that DGK zeta is involved in IQGAP1/Rac1-mediated phagocytosis upon LPS stimulation in macrophages. (C) 2012 Elsevier Inc. All rights reserved.