mTOR signaling: PLD takes center stage

Sun, Yuting; Chen, Jiawen

doi:10.4161/cc.7.20.6881

Cited by 75 publications

(76 citation statements)

References 79 publications

(133 reference statements)

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“…Mutations in lipin 1 PAP activity would be predicted to increase the cellular PA concentration, which may be toxic and/or activate inflammatory MAPK signaling cascades (Nadra et al 2008). PA also activates mTORC1 kinase (Sun and Chen 2008;Mitra et al 2013), which has been linked to development of muscle injury and myopathy (Castets et al 2013) Leu635Pro (*P < 0.05, t-test). (c) Coomassie stain and PAP activity of purified recombinant WT lipin 1, p.Leu635Pro, and p.Arg725His.…”

Section: Discussionmentioning

confidence: 99%

Rhabdomyolysis-Associated Mutations in Human LPIN1 Lead to Loss of Phosphatidic Acid Phosphohydrolase Activity

et al. 2015

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Section: Discussionmentioning

confidence: 99%

Rhabdomyolysis-Associated Mutations in Human LPIN1 Lead to Loss of Phosphatidic Acid Phosphohydrolase Activity

et al. 2015

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“…PA has also been shown to influence the oligomerization of mTORC1 and mTORC2 complexes, with potential consequences on their activities (43). Another proposed mechanism of mTOR activation by PA involves the displacement of the inhibitory protein FKBP38 by competition for the same binding site (5). However, the role of FKBP38 in mTOR regulation has been recently questioned (44).…”

Section: Discussionmentioning

confidence: 99%

“…A recently identified regulatory signal impacting on mTOR activity is the production of phosphatidic acid (PA) by phospholipase D (PLD)-mediated hydrolysis of phosphatidylcholine (5,6). PLD, which can be activated by a variety of hormones, growth factors, and cytokines, is present in most tissues under two isoforms, PLD1 and PLD2, endowed with different properties, regulations, and functions (7).…”

Section: The Mammalian Target Of Rapamycin (Mtor)mentioning

confidence: 99%

Phospholipase D Regulates Myogenic Differentiation through the Activation of Both mTORC1 and mTORC2 Complexes

Jaafar

Zeiller

Pirola

et al. 2011

Journal of Biological Chemistry

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How phospholipase D (PLD) is involved in myogenesis remains unclear. At the onset of myogenic differentiation of L6 cells induced by the PLD agonist vasopressin in the absence of serum, mTORC1 complex was rapidly activated, as reflected by phosphorylation of S6 kinase1 (S6K1). Both the long (p85) and short (p70) S6K1 isoforms were phosphorylated in a PLD1-dependent way. Short rapamycin treatment specifically inhibiting mTORC1 suppressed p70 but not p85 phosphorylation, suggesting that p85 might be directly activated by phosphatidic acid. Vasopressin stimulation also induced phosphorylation of Akt on Ser-473 through PLD1-dependent activation of mTORC2 complex. In this model of myogenesis, mTORC2 had a positive role mostly unrelated to Akt activation, whereas mTORC1 had a negative role, associated with S6K1-induced Rictor phosphorylation. The PLD requirement for differentiation can thus be attributed to its ability to trigger via mTORC2 activation the phosphorylation of an effector that could be PKC␣. Moreover, PLD is involved in a counter-regulation loop expected to limit the response. This study thus brings new insights in the intricate way PLD and mTOR cooperate to control myogenesis.The mammalian target of rapamycin (mTOR) 2 is a serine/ threonine protein kinase that integrates signals provided by growth factors, nutrient availability, energy levels, or redox status to adapt protein synthesis and major cell functions such as growth, proliferation, and survival to the physiological conditions (1). It exists in two complexes, mTORC1 and mTORC2, that are differentially regulated, have distinct effector substrates, and are differentially sensitive to rapamycin, a bacterial macrolide endowed with anti-proliferative and immunosuppressant activities. Whereas activity of mTORC1 complex is highly sensitive to acute treatment by nanomolar concentrations of rapamycin, only prolonged rapamycin treatment is able to induce mTORC2 disruption and inactivation (2-4).A recently identified regulatory signal impacting on mTOR activity is the production of phosphatidic acid (PA) by phospholipase D (PLD)-mediated hydrolysis of phosphatidylcholine (5, 6). PLD, which can be activated by a variety of hormones, growth factors, and cytokines, is present in most tissues under two isoforms, PLD1 and PLD2, endowed with different properties, regulations, and functions (7). Phosphatidic acid has been shown to specifically bind to mTOR protein on the FRB domain, a regulatory site also responsible for the binding of rapamycin in complex with protein FKBP12. The protein/ phospholipid interaction causes the activation of mTOR kinase, and rapamycin has been proposed to exert its inhibitory effects on mTOR by competing with PA and blocking PA-mediated activation (8 -10).Signaling by mTOR has become a topic of particular interest in the field of skeletal muscle biology due to the critical involvement of this kinase in muscle remodeling. Thus, muscle hypertrophy induced by exercise has been shown to involve mTOR signaling (11-13). Rapamycin inhibits...

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“…Although somewhat controversial, mitogen-stimulated production of the lipid second messenger phosphatidic acid via the enzyme phospholipase D promotes mTORC1 signaling via poorly defined mechanisms, possibly by binding the mTOR FRB domain (52). Moreover, phosphatidic acid may aid mTORC1 and mTORC2 complex assembly and compete with rapamycin for mTOR binding, providing a potential explanation for why cancer cells, which often possess high phospholipase D activity, display variable resistance to rapamycin (53,54).…”

Section: Regulation Of Mtorc Signaling Networkmentioning

confidence: 99%

Mammalian Target of Rapamycin (mTOR): Conducting the Cellular Signaling Symphony

Foster

Fingar

2010

Journal of Biological Chemistry

474

458

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The mammalian target of rapamycin (mTOR) protein kinase responds to diverse environmental cues to control a plethora of cellular processes. mTOR forms the catalytic core of at least two distinct signaling complexes known as mTOR complexes 1 and 2. Differing sensitivities to the mTOR inhibitor rapamycin, unique partner proteins, distinct substrates, and unique cellular functions distinguish the complexes. Here, we review recent progress in our understanding of the regulation and function of mTOR signaling networks in cellular physiology.

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mTOR signaling: PLD takes center stage

Cited by 75 publications

References 79 publications

Rhabdomyolysis-Associated Mutations in Human LPIN1 Lead to Loss of Phosphatidic Acid Phosphohydrolase Activity

Rhabdomyolysis-Associated Mutations in Human LPIN1 Lead to Loss of Phosphatidic Acid Phosphohydrolase Activity

Phospholipase D Regulates Myogenic Differentiation through the Activation of Both mTORC1 and mTORC2 Complexes

Mammalian Target of Rapamycin (mTOR): Conducting the Cellular Signaling Symphony

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