PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals

Sang Hoon Ha, Do Hyung Kim, Il Shin Kim, Jung Hwan Kim, Mi Nam Lee, Hyun Ju Lee, Jong Heon Kim, Sung Key Jang, Pann Ghill Suh, Sung Ho Ryu

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Mammalian target-of-rapamycin (mTOR), which is a master controller of cell growth, senses a mitogenic signal in part through the lipid second messenger phosphatidic acid (PA), generated by phospholipase D (PLD). To understand further which isozymes of PLD are involved in this process, we compared the effect of PLD isozymes on mTOR activation. We found that PLD2 has an essential role in mitogen-induced mTOR activation as the siRNA-mediated knockdown of PLD2, not of PLD1, profoundly reduced the phosphorylations of S6K1 and 4EBP1, well-known mTOR effectors. Furthermore, exogenous PA-induced mTOR activation was abrogated by PLD2 knockdown, but not by PLD1 knockdown. This abrogation was found to be the result of complex formation between PLD2 and mTOR/raptor. PLD2 possesses a TOS-like motif (Phe-Glu-Val-Gln-Val, a.a. 265-269), through which it interacts with raptor independently of the other TOS motif-containing proteins, S6K1 and 4EBP1. PLD2-dependent mTOR activation appears to require PLD2 binding to mTOR/raptor with lipase activity, since lipase-inactive PLD2 cannot trigger mTOR activation despite its ability to interact with mTOR/raptor. Abrogation of mitogen-dependent mTOR activation by PLD2 knockdown was rescued only by wild type PLD2, but not by raptor binding-deficient and lipase-inactive PLD2. Our results demonstrate the importance of localized PA generation for the mitogen-induced activation of mTOR, which is achieved by a specific interaction between PLD2 and mTOR/raptor.

Original languageEnglish (US)
Pages (from-to)2283-2291
Number of pages9
JournalCellular Signalling
Volume18
Issue number12
DOIs
StatePublished - Dec 1 2006

Fingerprint

Raptors
Sirolimus
Phospholipase D
Phosphatidic Acids
Lipase
Mitogens
Isoenzymes
Amino Acid Motifs
Second Messenger Systems

Keywords

  • Complex formation
  • PLD2
  • Raptor
  • mTOR

Cite this

Ha, S. H., Kim, D. H., Kim, I. S., Kim, J. H., Lee, M. N., Lee, H. J., ... Ryu, S. H. (2006). PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals. Cellular Signalling, 18(12), 2283-2291. https://doi.org/10.1016/j.cellsig.2006.05.021

PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals. / Ha, Sang Hoon; Kim, Do Hyung; Kim, Il Shin; Kim, Jung Hwan; Lee, Mi Nam; Lee, Hyun Ju; Kim, Jong Heon; Jang, Sung Key; Suh, Pann Ghill; Ryu, Sung Ho.

In: Cellular Signalling, Vol. 18, No. 12, 01.12.2006, p. 2283-2291.

Research output: Contribution to journalArticle

Ha, SH, Kim, DH, Kim, IS, Kim, JH, Lee, MN, Lee, HJ, Kim, JH, Jang, SK, Suh, PG & Ryu, SH 2006, 'PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals', Cellular Signalling, vol. 18, no. 12, pp. 2283-2291. https://doi.org/10.1016/j.cellsig.2006.05.021
Ha, Sang Hoon ; Kim, Do Hyung ; Kim, Il Shin ; Kim, Jung Hwan ; Lee, Mi Nam ; Lee, Hyun Ju ; Kim, Jong Heon ; Jang, Sung Key ; Suh, Pann Ghill ; Ryu, Sung Ho. / PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals. In: Cellular Signalling. 2006 ; Vol. 18, No. 12. pp. 2283-2291.
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AU - Ha, Sang Hoon

AU - Kim, Do Hyung

AU - Kim, Il Shin

AU - Kim, Jung Hwan

AU - Lee, Mi Nam

AU - Lee, Hyun Ju

AU - Kim, Jong Heon

AU - Jang, Sung Key

AU - Suh, Pann Ghill

AU - Ryu, Sung Ho

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AB - Mammalian target-of-rapamycin (mTOR), which is a master controller of cell growth, senses a mitogenic signal in part through the lipid second messenger phosphatidic acid (PA), generated by phospholipase D (PLD). To understand further which isozymes of PLD are involved in this process, we compared the effect of PLD isozymes on mTOR activation. We found that PLD2 has an essential role in mitogen-induced mTOR activation as the siRNA-mediated knockdown of PLD2, not of PLD1, profoundly reduced the phosphorylations of S6K1 and 4EBP1, well-known mTOR effectors. Furthermore, exogenous PA-induced mTOR activation was abrogated by PLD2 knockdown, but not by PLD1 knockdown. This abrogation was found to be the result of complex formation between PLD2 and mTOR/raptor. PLD2 possesses a TOS-like motif (Phe-Glu-Val-Gln-Val, a.a. 265-269), through which it interacts with raptor independently of the other TOS motif-containing proteins, S6K1 and 4EBP1. PLD2-dependent mTOR activation appears to require PLD2 binding to mTOR/raptor with lipase activity, since lipase-inactive PLD2 cannot trigger mTOR activation despite its ability to interact with mTOR/raptor. Abrogation of mitogen-dependent mTOR activation by PLD2 knockdown was rescued only by wild type PLD2, but not by raptor binding-deficient and lipase-inactive PLD2. Our results demonstrate the importance of localized PA generation for the mitogen-induced activation of mTOR, which is achieved by a specific interaction between PLD2 and mTOR/raptor.

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