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Gene Review

PLD2  -  phospholipase D2

Homo sapiens

Synonyms: Choline phosphatase 2, PLD 2, PLD1C, Phosphatidylcholine-hydrolyzing phospholipase D2, Phospholipase D2, ...
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Disease relevance of PLD2

  • In our present study we investigated how PLD2 activity is regulated in mouse lymphocytic leukemia L1210 cells, which mainly contain PLD2, and in PLD2 -transfected COS-7 cells [1].
  • We conclude that oleic acid is a selective activator of PLD2 and can be used for localization studies, but its use as an activator of PLD2 in intact cells to study function is limited due to toxicity [2].
  • These results suggest that EWS-Fli1 may play a role in the regulation of tumor proliferation-signaling enzymes via PLD2 expression in Ewing sarcoma cells [3].
  • Thus, this study was conducted to determine the activity and the expression of PLD2 in human colorectal cancer [4].
  • As determined by reverse transcription polymerase chain reaction, both splicing variants of PLD1, PLD1a and PLD1b, and the isoenzyme PLD2, are expressed in melanoma cells and melanocytes [5].

High impact information on PLD2


Chemical compound and disease context of PLD2


Biological context of PLD2


Anatomical context of PLD2

  • In contrast, overexpressed mouse PLD2 was observed to localize primarily to the plasma membrane, although internalization on membrane vesicles was observed subsequent to serum stimulation [16].
  • Finally, alpha-actinin co-localizes with actin and with PLD2 in the detergent-insoluble fraction from sarcolemmal membranes [17].
  • Intriguingly, A23187, a calcium ionophore that induces calcium influx, potently stimulates PLD activity in these two cell lines, suggesting that Ca2+ might be implicated in the regulation of the PLD2 activity [1].
  • Examination of membranes prepared from COS-7, Jurkat and HL60 cells indicated a relationship between oleate-stimulated PLD2 activity and PLD2 immunoreactivity [2].
  • Here we show that caveolin-rich fractions, prepared from HaCaT human keratinocytes by either detergent-based or detergent-free methods, contain PLD2 [18].

Associations of PLD2 with chemical compounds

  • Conversely the inhibition of PLD2-mediated phosphatidic acid formation by 1-butanol or overexpression of a negative mutant of PLD2 prevented agonist-mediated endocytosis of MOR1 [12].
  • The inhibitory effect of arachidonyl trifluoromethyl ketone on the A23187-induced PLD2 activity could be recovered by addition of exogenous lysophosphatidylcholine [1].
  • Furthermore, heterologous stimulation of PLD2 by phorbol ester led to an accelerated internalization of the mu-opioid receptor after both DAMGO and morphine exposure [12].
  • Mutation of this residue to phenylalanine enhanced basal activity almost 2-fold, but did not alter the magnitude of the EGF-mediated increase in PLD2 activity [19].
  • Finally, studies conducted using overexpression of wild-type active or dominant-negative isoforms of PLD2 and RNA interference-mediated targeting of PLD2 suggest that PLD2 functions at the plasma membrane to facilitate endocytosis of the angiotensin II type 1 receptor [16].

Physical interactions of PLD2

  • In this study, we have examined the properties of the PX domains of PLD1 and PLD2 in terms of phosphoinositide binding and PLD activity regulation [20].
  • We also determined that the region between amino acids 613 and 723 of PLD2 is required for the direct binding of beta-actin, using bacterially expressed glutathione S-transferase fusion proteins of PLD2 fragments [21].
  • PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals [22].
  • PLD2 co-immunoprecipitated with ERK1/2 and became phosphorylated on MAP kinase consensus sites in fMLP-stimulated cells [23].

Enzymatic interactions of PLD2

  • In cell-free systems, ERK2 gave rise to strong ATP-dependent PLD activity and directly phosphorylated PLD2 that generated two phosphopeptides only after tryptic digestion [23].

Regulatory relationships of PLD2


Other interactions of PLD2


Analytical, diagnostic and therapeutic context of PLD2


  1. Cytosolic phospholipase A2-mediated regulation of phospholipase D2 in leukocyte cell lines. Kim, J.H., Lee, B.D., Kim, Y., Lee, S.D., Suh, P.G., Ryu, S.H. J. Immunol. (1999) [Pubmed]
  2. Endogenous phospholipase D2 localizes to the plasma membrane of RBL-2H3 mast cells and can be distinguished from ADP ribosylation factor-stimulated phospholipase D1 activity by its specific sensitivity to oleic acid. Sarri, E., Pardo, R., Fensome-Green, A., Cockcroft, S. Biochem. J. (2003) [Pubmed]
  3. Inhibition of platelet-derived growth factor-induced cell growth signaling by a short interfering RNA for EWS-Fli1 via down-regulation of phospholipase D2 in Ewing sarcoma cells. Nozawa, S., Ohno, T., Banno, Y., Dohjima, T., Wakahara, K., Fan, D.G., Shimizu, K. J. Biol. Chem. (2005) [Pubmed]
  4. Increased activity and expression of phospholipase D2 in human colorectal cancer. Oshimoto, H., Okamura, S., Yoshida, M., Mori, M. Oncol. Res. (2003) [Pubmed]
  5. Expression and regulation of phospholipase D isoenzymes in human melanoma cells and primary melanocytes. Riebeling, C., Müller, C., Geilen, C.C. Melanoma Res. (2003) [Pubmed]
  6. The phox homology domain of phospholipase D activates dynamin GTPase activity and accelerates EGFR endocytosis. Lee, C.S., Kim, I.S., Park, J.B., Lee, M.N., Lee, H.Y., Suh, P.G., Ryu, S.H. Nat. Cell Biol. (2006) [Pubmed]
  7. Dual role for phosphoinositides in regulation of yeast and mammalian phospholipase D enzymes. Sciorra, V.A., Rudge, S.A., Wang, J., McLaughlin, S., Engebrecht, J., Morris, A.J. J. Cell Biol. (2002) [Pubmed]
  8. Interaction of the type Ialpha PIPkinase with phospholipase D: a role for the local generation of phosphatidylinositol 4, 5-bisphosphate in the regulation of PLD2 activity. Divecha, N., Roefs, M., Halstead, J.R., D'Andrea, S., Fernandez-Borga, M., Oomen, L., Saqib, K.M., Wakelam, M.J., D'Santos, C. EMBO J. (2000) [Pubmed]
  9. Phagocyte cell migration is mediated by phospholipases PLD1 and PLD2. Lehman, N., Di Fulvio, M., McCray, N., Campos, I., Tabatabaian, F., Gomez-Cambronero, J. Blood (2006) [Pubmed]
  10. Phosphorylation-dependent regulation of phospholipase D2 by protein kinase C delta in rat Pheochromocytoma PC12 cells. Han, J.M., Kim, J.H., Lee, B.D., Lee, S.D., Kim, Y., Jung, Y.W., Lee, S., Cho, W., Ohba, M., Kuroki, T., Suh, P.G., Ryu, S.H. J. Biol. Chem. (2002) [Pubmed]
  11. Transmodulation between phospholipase D and c-Src enhances cell proliferation. Ahn, B.H., Kim, S.Y., Kim, E.H., Choi, K.S., Kwon, T.K., Lee, Y.H., Chang, J.S., Kim, M.S., Jo, Y.H., Min, d.o. .S. Mol. Cell. Biol. (2003) [Pubmed]
  12. ADP-ribosylation factor-dependent phospholipase D2 activation is required for agonist-induced mu-opioid receptor endocytosis. Koch, T., Brandenburg, L.O., Schulz, S., Liang, Y., Klein, J., Hollt, V. J. Biol. Chem. (2003) [Pubmed]
  13. Involvement of phospholipase D2 in lysophosphatidate-induced transactivation of platelet-derived growth factor receptor-beta in human bronchial epithelial cells. Wang, L., Cummings, R., Zhao, Y., Kazlauskas, A., Sham, J.K., Morris, A., Georas, S., Brindley, D.N., Natarajan, V. J. Biol. Chem. (2003) [Pubmed]
  14. Cloning and initial characterization of a human phospholipase D2 (hPLD2). ADP-ribosylation factor regulates hPLD2. Lopez, I., Arnold, R.S., Lambeth, J.D. J. Biol. Chem. (1998) [Pubmed]
  15. Phospholipase D2 activity suppresses hydrogen peroxide-induced apoptosis in PC12 cells. Lee, S.D., Lee, B.D., Han, J.M., Kim, J.H., Kim, Y., Suh, P.G., Ryu, S.H. J. Neurochem. (2000) [Pubmed]
  16. Phospholipase D2 localizes to the plasma membrane and regulates angiotensin II receptor endocytosis. Du, G., Huang, P., Liang, B.T., Frohman, M.A. Mol. Biol. Cell (2004) [Pubmed]
  17. Cardiac phospholipase D2 localizes to sarcolemmal membranes and is inhibited by alpha-actinin in an ADP-ribosylation factor-reversible manner. Park, J.B., Kim, J.H., Kim, Y., Ha, S.H., Yoo, J.S., Du, G., Frohman, M.A., Suh, P.G., Ryu, S.H. J. Biol. Chem. (2000) [Pubmed]
  18. Phospholipase D2: functional interaction with caveolin in low-density membrane microdomains. Czarny, M., Fiucci, G., Lavie, Y., Banno, Y., Nozawa, Y., Liscovitch, M. FEBS Lett. (2000) [Pubmed]
  19. PLD2 complexes with the EGF receptor and undergoes tyrosine phosphorylation at a single site upon agonist stimulation. Slaaby, R., Jensen, T., Hansen, H.S., Frohman, M.A., Seedorf, K. J. Biol. Chem. (1998) [Pubmed]
  20. Phosphatidylinositol (3,4,5)-trisphosphate specifically interacts with the phox homology domain of phospholipase D1 and stimulates its activity. Lee, J.S., Kim, J.H., Jang, I.H., Kim, H.S., Han, J.M., Kazlauskas, A., Yagisawa, H., Suh, P.G., Ryu, S.H. J. Cell. Sci. (2005) [Pubmed]
  21. Actin directly interacts with phospholipase D, inhibiting its activity. Lee, S., Park, J.B., Kim, J.H., Kim, Y., Kim, J.H., Shin, K.J., Lee, J.S., Ha, S.H., Suh, P.G., Ryu, S.H. J. Biol. Chem. (2001) [Pubmed]
  22. PLD2 forms a functional complex with mTOR/raptor to transduce mitogenic signals. Ha, S.H., Kim, D.H., Kim, I.S., Kim, J.H., Lee, M.N., Lee, H.J., Kim, J.H., Jang, S.K., Suh, P.G., Ryu, S.H. Cell. Signal. (2006) [Pubmed]
  23. A role of p44/42 mitogen-activated protein kinases in formyl-peptide receptor-mediated phospholipase D activity and oxidant production. Paruch, S., El-Benna, J., Djerdjouri, B., Marullo, S., Périanin, A. FASEB J. (2006) [Pubmed]
  24. Transcriptional repression of cyclin-dependent kinase inhibitor p21 gene by phospholipase D1 and D2. Kwun, H.J., Lee, J.H., Min, d.o. .S., Jang, K.L. FEBS Lett. (2003) [Pubmed]
  25. Phospholipase D2-derived phosphatidic acid binds to and activates ribosomal p70 S6 kinase independently of mTOR. Lehman, N., Ledford, B., Di Fulvio, M., Frondorf, K., McPhail, L.C., Gomez-Cambronero, J. FASEB J. (2007) [Pubmed]
  26. ADP-ribosylation factor-dependent phospholipase D activation by the M3 muscarinic receptor. Mitchell, R., Robertson, D.N., Holland, P.J., Collins, D., Lutz, E.M., Johnson, M.S. J. Biol. Chem. (2003) [Pubmed]
  27. Insulin-induced phospholipase D1 and phospholipase D2 activity in human embryonic kidney-293 cells mediated by the phospholipase C gamma and protein kinase C alpha signalling cascade. Slaaby, R., Du, G., Altshuller, Y.M., Frohman, M.A., Seedorf, K. Biochem. J. (2000) [Pubmed]
  28. Changes in phospholipase D isoform activity and expression in multidrug-resistant human cancer cells. Fiucci, G., Czarny, M., Lavie, Y., Zhao, D., Berse, B., Blusztajn, J.K., Liscovitch, M. Int. J. Cancer (2000) [Pubmed]
  29. Regulation of phospholipase D2 activity by protein kinase C alpha. Chen, J.S., Exton, J.H. J. Biol. Chem. (2004) [Pubmed]
  30. Activation of phospholipase D by bradykinin and sphingosine 1-phosphate in A549 human lung adenocarcinoma cells via different GTP-binding proteins and protein kinase C delta signaling pathways. Meacci, E., Nuti, F., Catarzi, S., Vasta, V., Donati, C., Bourgoin, S., Bruni, P., Moss, J., Vaughan, M. Biochemistry (2003) [Pubmed]
  31. Effect of priming on activation and localization of phospholipase D-1 in human neutrophils. Cadwallader, K.A., Uddin, M., Condliffe, A.M., Cowburn, A.S., White, J.F., Skepper, J.N., Ktistakis, N.T., Chilvers, E.R. Eur. J. Biochem. (2004) [Pubmed]
  32. Phospholipase D2 acts as an essential adaptor protein in the activation of Syk in antigen-stimulated mast cells. Lee, J.H., Kim, Y.M., Kim, N.W., Kim, J.W., Her, E., Kim, B.K., Kim, J.H., Ryu, S.H., Park, J.W., Seo, D.W., Han, J.W., Beaven, M.A., Choi, W.S. Blood (2006) [Pubmed]
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