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Molecular and Cellular Biology, April 2005, p. 3194-3208, Vol. 25, No. 8
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.8.3194-3208.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Novel Functions of the Phospholipase D2-Phox Homology Domain in Protein Kinase C{zeta} Activation{dagger}

Jong Hyun Kim,1 Jung Hwan Kim,1 Motoi Ohba,2 Pann-Ghill Suh,1 and Sung Ho Ryu1*

Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea,1 Institute of Molecular Oncology, Showa University, Shinagawa-ku, Tokyo, Japan2

Received 1 June 2004/ Returned for modification 2 August 2004/ Accepted 7 January 2005

It has been established that protein kinase C{zeta} (PKC{zeta}) participates in diverse signaling pathways and cellular functions in a wide variety of cells, exhibiting properties relevant to cellular survival and proliferation. Currently, however, the regulation mechanism of PKC{zeta} remains elusive. Here, for the first time, we determine that phospholipase D2 (PLD2) enhances PKC{zeta} activity through direct interaction in a lipase activity-independent manner. This interaction of the PLD2-Phox homology (PX) domain with the PKC{zeta}-kinase domain also induces the activation loop phosphorylation of PKC{zeta} and downstream signal stimulation, as measured by p70 S6 kinase phosphorylation. Furthermore, only the PLD2-PX domain directly stimulates PKC{zeta} activity in vitro, and it is necessary for the formation of the ternary complex with phosphoinositide-dependent kinase 1 and PKC{zeta}. The mutant that substitutes the triple lysine residues (Lys101, Lys102, and Lys103) within the PLD2-PX domain with alanine abolishes interaction with the PKC{zeta}-kinase domain and activation of PKC{zeta}. Moreover, breast cancer cell viability is significantly affected by PLD2 silencing. Taken together, these results suggest that the PLD2-mediated PKC{zeta} activation is induced by its PX domain performing both direct activation of PKC{zeta} and assistance of activation loop phosphorylation. Furthermore, we find it is an important factor in the survival of breast cancer cells.

* Corresponding author. Mailing address: Division of Molecular and Life Sciences, Pohang University of Science and Technology, San 31, Hyojadong, Pohang 790-784, Republic of Korea. Phone: 82-54-279-2292. Fax: 82-54-279-0645. E-mail: sungho{at}postech.ac.kr.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2005, p. 3194-3208, Vol. 25, No. 8
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.8.3194-3208.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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