Implication of Phospholipase D2 in Oxidant-induced Phosphoinositide 3-Kinase Signaling via Pyk2 Activation in PC12 Cells

Banno, Yoshiko; Ohguchi, Ken-ichi; Matsumoto, Naoki; Koda, Masahiro; Ueda, Masashi; Hara, Akira; Đikić, Ivan; Nozawa, Yoshinori

doi:10.1074/jbc.m410903200

Cited by 27 publications

(22 citation statements)

References 38 publications

(42 reference statements)

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“…Interestingly, the PLD2 sequence 169 YLNRLLT 175 overlaps with the predicted phosphorylation site for Akt kinase (( L / R )X( L / R )XX( pS / pT )) (Liu et al, 2002). As known, the PI3K/Akt cell survival pathway can be activated by Ras, as well as by PLD2 (Banno et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

The elucidation of novel SH2 binding sites on PLD2

et al. 2006

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Section: Discussionmentioning

confidence: 99%

The elucidation of novel SH2 binding sites on PLD2

et al. 2006

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“…PLD also activates STAT3 by interacting with the thyroid oncogenic kinase RET/PTC (29). PLD2 can form a complex with the EGF receptor (EGFR) (12,46) or with Pyk2 and Src kinases (4). Hydrogen peroxide and EGF induce PLD phosphorylation and PKC-␣ activation (38), while activation of PLD by 8-Br-cAMP is accomplished through Src, Ras, and ERK (49).…”

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confidence: 99%

A Comprehensive Model That Explains the Regulation of Phospholipase D2 Activity by Phosphorylation-Dephosphorylation

Henkels

Peng

Frondorf

et al. 2010

Molecular and Cellular Biology

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We report here that the enzymatic activity of phospholipase D2 (PLD2) is regulated by phosphorylationdephosphorylation. Phosphatase treatment of PLD2-overexpressing cells showed a biphasic nature of changes in activity that indicated the existence of "activator" and "inhibitory" sites. We identified three kinases capable of phosphorylating PLD2 in vitro-epidermal growth factor receptor (EGFR), JAK3, and Src (with JAK3 reported for the first time in this study)-that phosphorylate an inhibitory, an activator, and an ambivalent (one that can yield either effect) site, respectively. Mass spectrometry analyses indicated the target of each of these kinases as Phospholipase D2 (PLD) catalyzes the hydrolysis of phosphatidylcholine to generate the lipid second messenger phosphatidic acid (PA) and choline. There are two mammalian isoforms: PLD1 (20) and PLD2 (12, 33). They share a highly conserved "HKD" domain necessary for catalysis (39). PLD has been implicated in a variety of physiological cellular functions, such as intracellular protein trafficking, cytoskeletal dynamics, membrane remodeling, and cell proliferation in mammalian cells and meiotic division and sporulation in yeast (6,15,16,32,42). PLD regulation in cells falls into two major signaling categories. One is by the small GTPase proteins Arf and Rho (3,5,11,43), and the other is by growth factors/ mitogens such as epidermal growth factor (EGF), plateletderived growth factor, insulin, and serum that implicate tyrosine kinases (2,12,21,22,34). Several gaps in knowledge of the second arm remain in spite of its importance in cell signaling. The isoform PLD1 can be phosphorylated on tyrosine, but this does not lead to changes in activity (35, 36).The isoform PLD2, which is expressed as a constitutively active enzyme in many cell types (47), can be detected as a phosphotyrosine protein both in vivo (25) and in vitro (17,25,41). PLD2 overexpression induces the transformation of cells (27,34,37,48), and the activation of this enzyme enhances cellular processes favorable for the metastasis of EL4 lymphoma cells (30). PLD also activates STAT3 by interacting with the thyroid oncogenic kinase RET/PTC (29). PLD2 can form a complex with the EGF receptor (EGFR) (12, 46) or with Pyk2 and Src kinases (4). Hydrogen peroxide and EGF induce PLD phosphorylation and PKC-␣ activation (38), while activation of PLD by 8-Br-cAMP is accomplished through Src, Ras, and ERK (49).Although all of these studies agree with respect to the presence of tyrosine kinases in PLD signaling, different conclusions were drawn regarding lipase activity. For example, whereas coexpression of PLD2 and Fyn or Fgr kinases lead to an enhancement of PLD activation and degranulation of mast cells (10), Ho et al. (23) , and Y 470 are important for PLD2 function (10) but, nevertheless, the overexpression of the phosphorylation-deficient mutant, PLD2-Y11F, increases PLD2 activity in resting or EGFactivated cells (12).Closely related to the enhancing effect of phosphorylationdeficient mutants, a new line of rese...

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“…The relevance of PLD2 in cell proliferation has been reported earlier [reviewed in [2,43]]. Transient expression of PLD2 WT per se does not increase de novo DNA synthesis [3,25], but provides survival signals by phosphorylation of AKT in a PI3K-dependent manner [24,[38][39][40][41][42] thus preventing uncontrolled cell proliferation [32]. We show here that transient expression of PLD2 WT or Y179F in COS7 cells resulted in increased AKT phosphorylation in residues T 308 /S 473 in a PI3K-dependent manner.…”

Section: Discussionmentioning

confidence: 83%

“…Interestingly, most of these effectors can also be regulated by PLD [16,21,22,25,[33][34][35][36]. Furthermore, AKT and bacterial PLD interact [37] and PLD plays a critical role in the PI3K-dependent activation of AKT [38][39][40][41][42]. The addition of exogenous bacterial PLD to CHO cells results in AKT activation in a PA-and PI3K-dependent manner [43].…”

Section: Introductionmentioning

confidence: 99%

Mutation of Y179 on phospholipase D2 (PLD2) upregulates DNA synthesis in a PI3K-and Akt-dependent manner

Fulvio

Frondorf

Gómez‐Cambronero

2008

Cellular Signalling

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Phospholipase D2 (PLD2), one of the two mammalian members of the PLD family, has been implicated in cell proliferation, transformation, tumor progression and survival. However, as precise mechanistic details are still unknown, we investigated here if the PLD2 isoform would signal through the PI3K/AKT pathway. Transient expression of PLD2 in COS7 cells with either the WT or with a Y179F mutant, resulted in an increased basal phosphorylation of AKT in residues T 308 and S 473 , in a PI3K-dependent manner. Transfection of PLD2-Y179F (but not the wild type) caused an increased (>2-fold) DNA synthesis even in the absence of extracellular stimuli. Other signaling mechanisms downstream such PLD/PI3K dependence (that might lead to DNA synthesis regulation), were further studied. PLD2-Y179F caused an increase in phosphorylation of p42/p44 ERK and in the expression of G 0 /G 1 phase transition markers, p21 CIP and PCNA, and these effects, too, were dependent on PI3K. Interestingly, Akt once activated, enabled the phosphorylation of PLD2 on residue T 175 , an effect that was inhibited by LY296004. Lastly, if PLD2-Y179F is further mutated in residue K758 (PLD2 Y179F-K758R), which renders inactive a catalytic site, DNA synthesis is then abrogated, indicating that the activity of the enzyme (i.e. synthesis of PA) is necessary for the observed effects.In conclusion, the unavailability of residue Y179 on PLD2 to become phosphorylated leads to an augmentation of DNA synthesis concomitantly with MEK and AKT phosphorylation, in a process that is dependent on PI3K and independent of any extracellular stimuli. This might be critical for the maintenance of the PLD2-regulated proliferative status.

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Implication of Phospholipase D2 in Oxidant-induced Phosphoinositide 3-Kinase Signaling via Pyk2 Activation in PC12 Cells

Cited by 27 publications

References 38 publications

The elucidation of novel SH2 binding sites on PLD2

The elucidation of novel SH2 binding sites on PLD2

A Comprehensive Model That Explains the Regulation of Phospholipase D2 Activity by Phosphorylation-Dephosphorylation

Mutation of Y179 on phospholipase D2 (PLD2) upregulates DNA synthesis in a PI3K-and Akt-dependent manner

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