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Vol. 19, Issue 7, 3111-3123, July 2008

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Phospholipase D Activity Regulates Integrin-mediated Cell Spreading and Migration by Inducing GTP-Rac Translocation to the Plasma Membrane

Young Chan Chae^*, Jung Hwan Kim^*, Kyung Lock Kim^*, Hyun Wook Kim^*, Hye Young Lee^*, Won Do Heo, Tobias Meyer, Pann-Ghill Suh^*, and Sung Ho Ryu^*

*Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea; and Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, CA 94305

Submitted April 13, 2007; Revised April 18, 2008; Accepted May 1, 2008
Monitoring Editor: Martin A. Schwartz

Small GTPase Rac is a crucial regulator of actin cytoskeletal rearrangement, and it plays an important role in cell spreading, migration, mitogenesis, phagocytosis, superoxide generation, and axonal growth. It is generally accepted that Rac activity is regulated by the guanosine triphosphate (GTP)/guanosine diphosphate (GDP) cycle. But, it is suggested that in addition to Rac-GTP loading, membrane localization is required for the initiation of downstream effector signaling. However, the molecular mechanisms that control the targeting of GTP-Rac to the plasma membrane remain largely unknown. Here, we have uncovered a signaling pathway linking phospholipase D (PLD) to the localized functions of Rac1. We show that PLD product phosphatidic acid (PA) acts as a membrane anchor of Rac1. The C-terminal polybasic motif of Rac1 is responsible for direct interaction with PA, and Rac1 mutated in this region is incapable of translocating to the plasma membrane and of activating downstream target p21-activated kinase upon integrin activation. Finally, we show that PA induces dissociation of Rho-guanine nucleotide dissociation inhibitor from Rac1 and that PA-mediated Rac1 localization is important for integrin-mediated lamellipodia formation, cell spreading, and migration. These results provide a novel molecular mechanism for the GTP-Rac1 localization through the elevating PLD activity, and they suggest a general mechanism for diverse cellular functions that is required localized Rac activation.

Address correspondence to: Sung Ho Ryu (sungho{at}postech.ac.kr)

Abbreviations used: MMP, matrix metalloproteinase; PA, phosphatidic acid; PAK, p21-activated kinase; PBD, p21-binding domain; PIP₂, phosphatidylinositol 4,5-bisphosphate; PIP₃, phosphatidylinositol 3,4,5-triphosphate; PI3K, phosphoinositide 3-kinase; PLD, phospholipase D; TX, Triton X.