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Molecular and Cellular Biology, May 2003, p. 3103-3115, Vol. 23, No. 9
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.9.3103-3115.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Transmodulation between Phospholipase D and c-Src Enhances Cell Proliferation

Bong-Hyun Ahn,1 Shi Yeon Kim,1 Eun Hee Kim,2 Kyeong Sook Choi,2 Taeg Kyu Kwon,3 Young Han Lee,4 Jong-Soo Chang,5 Myung-Suk Kim,1 Yang-Hyeok Jo,1 and Do Sik Min1*

Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul,1 Laboratory of Endocrinology, Institute for Medical Sciences, Ajou University School of Medicine, Suwon,2 Department of Immunology, School of Medicine, Keimyung University,3 Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu,4 Department of Life Science, Daejin University, Pochon-gun, Kyeonggido, Korea5

Received 14 August 2002/ Returned for modification 9 September 2002/ Accepted 24 January 2003

Phospholipase D (PLD) has been implicated in the signal transduction pathways initiated by several mitogenic protein tyrosine kinases. We demonstrate for the first time that most notably PLD2 and to a lesser extent the PLD1 isoform are tyrosine phosphorylated by c-Src tyrosine kinase via direct association. Moreover, epidermal growth factor induced tyrosine phosphorylation of PLD2 and its interaction with c-Src in A431 cells. Interaction between these proteins is via the pleckstrin homology domain of PLD2 and the catalytic domain of c-Src. Coexpression of PLD1 or PLD2 with c-Src synergistically enhances cellular proliferation compared with expression of either molecule. While PLD activity as a lipid-hydrolyzing enzyme is not affected by c-Src, wild-type PLDs but not catalytically inactive PLD mutants significantly increase c-Src kinase activity, up-regulating c-Src-mediated paxillin phosphorylation and extracellular signal-regulated kinase activity. These results demonstrate the critical role of PLD catalytic activity in the stimulation of Src signaling. In conclusion, we provide the first evidence that c-Src acts as a kinase of PLD and PLD acts as an activator of c-Src. This transmodulation between c-Src and PLD may contribute to the promotion of cellular proliferation via amplification of mitogenic signaling pathways.

* Corresponding author. Mailing address: Department of Physiology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, Korea. Phone: 82 2-590-1165. Fax: 82 2-532-9575. E-mail: dsmin{at}cmc.cuk.ac.kr.

Molecular and Cellular Biology, May 2003, p. 3103-3115, Vol. 23, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.9.3103-3115.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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