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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1376.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Lysophosphatidylcholine Activates a Novel PKD2-Mediated Signaling Pathway That Controls Monocyte Migration

Mingqi Tan; Feng Hao; Xuemin Xu; Guy M. Chisolm; Mei-Zhen Cui

From the Department of Pathobiology (M.T., F.H., X.X., M.-Z.C.), the University of Tennessee College of Veterinary Medicine, Knoxville; and the Department of Cell Biology (G.M.C.), Lerner Research Institute, the Cleveland Clinic Foundation, Ohio.

Correspondence to Mei-Zhen Cui, PhD, Department of Pathobiology, the University of Tennessee College of Veterinary Medicine, 2407 River Drive, Knoxville, TN 37996. E-mail cuim{at}utk.edu

Objective— Monocyte activation and migration are crucial events in the development of atherosclerosis and other inflammatory diseases. This study examined the role of protein kinase D (PKD) in monocyte migration.

Method and Results— PKD2 is the predominant isoform of PKD expressed in monocytic THP-1 cells and primary human monocytes. Lysophosphatidylcholine (lysoPC), a prominent component of oxidized low-density lipoprotein, induces rapid and marked PKD activation in these cells. Using multiple approaches, including dominant-negative mutants and small interfering RNA knock-down, we found that lysoPC-induced PKD2 activation was required for the activation of both ERK and p38 MAPK. p38 MAPK mediation of lysoPC-induced monocytic cell migration was reported previously; our results reveal that the lysoPC-induced PKD2-p38 pathway controls monocyte migration.

Conclusions— This study provides the first evidence that (1) lysoPC activates PKD, (2) PKD2 has a novel role in p38 activation, and (3) the PKD2-activated p38 pathway is responsible for lysoPC-induced migration of THP-1 cells and human monocytes. Thus, PKD is a novel and functional intracellular regulator in both lysoPC signaling and monocyte migration. These results suggest a new role for PKD2 in the development of atherosclerosis and other inflammatory diseases.

Lysophosphatidylcholine activates protein kinase D (PKD), and the PKD2-activated p38 pathway is responsible for lysophosphatidylcholine-induced monocyte migration. Thus, PKD is a novel and functional intracellular regulator in lysophosphatidylcholine signaling, and PKD mediates monocyte migration. These results suggest a new role for PKD2 in the development of atherosclerosis.

Key Words: protein kinase • signaling pathway • lysophosphatidylcholine • monocyte migration