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A more recent version of this article appeared on November 1, 2002
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Submitted on February 22, 2002
Revised on July 29, 2002
Accepted on August 8, 2002
1 Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Korea
2 Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Korea (present address: The Rockefeller University, Laboratory of Molecular and Cellular Neuroscience, Box# 296,1230 York Avenue, New York, NY 10021, USA)
3 Institute of Molecular Oncology, Showa University, Tokyo, 142-8555, Japan
* Corresponding author. E-mail address: sungho{at}postech.ac.kr.
Phospholipase D (PLD) has been suggested to mediate epidermal growth factor (EGF) signaling. However, the molecular mechanism of EGF-induced PLD activation has not yet been elucidated. We investigated the importance of the phosphorylation and compartmentalization of PLD1 in EGF signaling. EGF treatment of COS-7 cells, transiently expressing PLD1, stimulated PLD1 activity and induced PLD1 phosphorylation. The EGF-induced phosphorylation of threonine 147 was completely blocked and the activity of PLD1 attenuated by point mutations (S2A/T147A/S561A) of PLD1 phosphorylation sites. The expression of a dominant negative PKC
mutant? by adenovirus-mediated gene transfer, greatly inhibited the phosphorylation and activation of PLD1 induced by EGF in PLD1 transfected COS-7 cells. EGF-induced PLD1 phosphorylation mainly occurred in the caveolin-enriched membrane (CEM) fraction, and the kinetics of PLD1 phosphorylation in the CEM were strongly correlated with PLD1 phosphorylation in the total membrane. Interestingly, EGF-induced PLD1 phosphorylation and activation, and the co-immunoprecipitation of PLD1 with caveolin-1 and the EGF receptor in the CEM were significantly attenuated in the palmitoylation-deficient C240S/C241S mutant, which did not localize to the CEM. Immunocytochemical analysis revealed that wild type PLD1 colocalized with caveolin-1 and the EGF receptor, and that phosphorylated PLD1 was exclusively localized in the plasma membrane, although some PLD1 was also detected in vesicular structures. Transfection of WT PLD1, but not of C240S/C241S mutant increased EGF-induced raf-1 translocation to the CEM and ERK phosphorylation. This study shows, for the first time that EGF-induced PLD1 phosphorylation and activation occur in the CEM and that the correct localization of PLD1 to the CEM via palmitoylation is critical for EGF signaling.
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