1 Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang 790-784, Korea
2 Schepens Eye Research Institute, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA
3 Graduate School of Life Science, University of Hyogo, Harima Science Garden City, Hyogo 678-1297, Japan
* Author for correspondence (e-mail: sungho{at}postech.ac.kr)
Accepted 28 June 2005
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Summary |
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Key words: PX domain, PLD, Phosphoinositides, ERK phosphorylation, PDGF
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Introduction |
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Phosphoinositide (PI) functions in diverse cellular processes (Martin, 1998; Odorizzi et al., 2000
). The D-myo-inositol head-group of PtdIns contains five hydroxyl groups (at positions 2, 3, 4, 5 and 6), three of which (3, 4, and 5) are known to be reversible phosphorylation targets to yield singly, doubly or triply phosphorylated phosphatidylinositide (PtdIns) derivatives (PtdIns3P, PtdIns4P, PtdIns5P, PtdIns(3,4)P2, PtdIns(3,5)P2, PtdIns(4,5)P2, and PtdIns(3,4,5)P3) of different combinations. The activities of specific PtdIns are regulated by controlling their cellular levels, which is achieved by complex networks of proteins that regulate their synthesis (kinases) and degradation (phosphatases and lipases) (De Camilli et al., 1996
; Fruman et al., 1998
; Rameh and Cantley, 1999
; Vanhaesebroeck et al., 2001
). Of these, PtdIns(3,4,5)P3 is synthesized when the mammalian class I phosphatidylinositide 3-kinase (PI3K) is recruited to the plasma membrane after the activation of a cell-surface-receptor kinase. The binding of PtdIns(3,4,5)P3 to its effector phosphoinositide-dependent kinase-1 (PDK-1) (Stokoe et al., 1997
) mediates the translocation of PDK-1 to a place where it can phosphorylate and activate Akt (protein kinase B, PKB) (Stephens et al., 1998
), which results in the increased phosphorylation of several substrates including glycogen synthase kinase-3 (GSK-3), p70s6k and 4E-BP1 (Scott et al., 1998
). These, in turn, activate diverse metabolic pathways and are necessary for cell survival (Stephens et al., 1998
). However, PtdIns-specific cellular functions, especially PtdIns(3,4,5)P3-induced molecular activation and signaling events, are not fully understood.
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PLD1 and PLD2 isozymes share several structural domains including the N-terminally localized PX domain (Frohman et al., 1999; Ponting, 1996
). Recently, Du et al. suggested that the PX domain of PLD1 plays a role in the re-entry of PLD1 into perinuclear vesicles after its PMA-stimulated translocation to the plasma membrane (Du et al., 2003
). However, the molecular characteristics of the PX domain of PLD, especially its role in the regulation of enzymatic activity, remains unclear. To check the phosphoinositide-binding ability of the PLD PX domain and to characterize the functional role of this interaction, we investigated the lipid affinity of PLD. Here, we show that the PLD1 PX domain specifically binds to PtdIns(3,4,5)P3, which is critical in PLD1 activity regulation.
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Materials and Methods |
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Cell culture
NIH-3T3, HEK 293 and HepG2 cells stably expressing mutant PDGFß receptor Y40/51 (Bae et al., 2000; Valius and Kazlauskas, 1993
) were cultured at 37°C in a humidified 5% CO2 atmosphere in high glucose DMEM supplemented with 10% fetal bovine serum.
Generation of plasmids and recombinant proteins
Mutants PLD1(R179K) or PLD1(R179A) were generated by point mutating the arginine residue in wild-type PLD1 at position 179 to lysine or alanine, respectively, by using the splice-overlap extension method (Ho et al., 1989). Briefly, PLD1(R179K) was obtained by using forward primer: 5'-G TTC TTT GGC AAG AGG CAA C-3' and reverse primer: 5'-G TTG CCT CTT GCC AAA GAA C-3'. A similar strategy was used to generate PLD1(R179A), this time by using forward primer: 5'-G TTC TTT GGC GCG AGG CAA C-3' and reverse primer: 5'-G TTG CCT CGC GCC AAA GAA C-3'. The resulting products were cloned into the pCDNA3.1 vector (Invitrogen). Sequences of the PLD1 PX domain (amino acids 76-196) of wild type, and mutants (R179K and R179A) were amplified by polymerase chain reaction (PCR) and subcloned into vector pGEX4T1 (Amersham Pharmacia Biotech) or pEGFP (enhanced green fluorescent protein)-C1 (pEGFP-C1, Clontech) vector to generate glutathione-S-transferase (GST)-PLD1 PX or EGFP-PLD1 PX constructs, respectively. To purify the recombinant proteins, Escherichia coli BL21 cells were transformed with individual expression vectors encoding GST fusion protein and grown at 37°C to an OD600 of 0.8. Fusion proteins were then induced by incubating the cells in the presence of 100 µM isopropyl-ß-D-thiogalactopyranoside for 4 hours at 25°C. After harvesting the cells, the fusion proteins were purified with glutathione-Sepharose 4B (Amersham Pharmacia Biotech).
Liposome-binding assay
Phospholipid-vesicles composed of 53 µM phosphatidylethanolamine (PE), 3.3 µM phosphatidylcholine, and 4.6 µM phosphoinositides (PtdIns) were incubated with 10 ng of the purified GST-PLD PX domains in 150 µl buffer A (50 mM Hepes-NaOH pH 7.5, 3 mM MgCl2, 2 mM CaCl2, 3 mM EGTA, and 80 mM KCl) as previously described (Kim et al., 1998). After incubation at 37°C for 15 minutes, the reaction mixtures were centrifuged at 300,000 g for 30 minutes in a TL-100 ultracentrifuge (Beckman). Supernatants and pellets were then subjected to SDS-PAGE and immunoblotted using anti-GST antibody. In competition analysis, water soluble inositolphosphates were added to incubation mixtures.
In vitro PLD activity assays
PLD activity was determined by measuring choline release from phosphatidylcholine as previously described (Kim et al., 1999) with a minor modification. The enzyme sources in this study were obtained from HEK 293 cells. Cells transfected with PLD1, PLD1(R179K), and PLD1(R179A) were harvested with buffer A. After sonication, 1 µg of lysate was used per assay.
In vivo PLD activity assays
PLD activity analysis was performed as previously described (Kim et al., 1999). Briefly, full-length PLD1 wild-type, PLD1(R179K) or PLD2 genes were transiently expressed. Transfection was carried out with LipofectAMINE, according to the manufacturer's instructions. In HEK 293 cells, depletion of endogenous PLD2 was performed using small interference RNA (siRNA) for PLD2, as described previously (Kim et al., 2005
). After starving the cells for 24 hours, they were incubated with 10 µCi [3H]myristic acid for 3 hours. PLD activity was determined using the transphosphatidylation reaction in the presence of 0.4% 1-butanol. Lipids were extracted and separated by Silica Gel 60 thin-layer chromatography (volume ratio of chloroform: methanol: acetic acid, 90:10:10), and the amounts of labeled phosphatidylbutanol and total lipid were determined using a Fuji BAS-2000 image analyzer (Fuji Film).
Immunocytochemistry and confocal imaging
NIH-3T3 cells grown on cover slips were transfected with pEGFP-PLD1 PX wild type, pEGFP-PLD1 PX (R179K) or pEGFP-PLD1 PX (R179A). After 24 hours of serum starvation, cells were treated with PDGF (25 ng/ml) and fixed with 4% (w/v) paraformaldehyde for 30 minutes. The slides were mounted and signals were visualized by confocal laser scanning microscopy (Zeiss LSM510, Germany).
Fractionation of cells
NIH-3T3 cells were washed twice with cold phosphate-buffered saline (PBS) and scraped with buffer B (PBS containing 0.25 M sucrose and a protease-inhibitor mixture). The cell suspension was then homogenized using a Dounce homogenizer and centrifuged at 3000 g for 15 minutes, and the supernatant was further centrifuged at 100,000 g for 30 minutes. The resulting supernatants (cytosol fraction) and pellets (membrane fraction) were subjected to SDS-PAGE and marked as Cyt and Mem, respectively.
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Results |
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The PLD1 PX domain interacts with PtdIns(3,4,5)P3 in NIH-3T3 cells
PI3K is known to catalyze the phosphorylation of the D-3 position of the inositol ring of phosphoinositides and to prefer PtdIns(4,5)P2 as its substrate, resulting in a high level of PtdIns(3,4,5)P3 in cells (Auger et al., 1989; Vanhaesebroeck et al., 2001
). With the obtained knowledge that PLD1PX has a high affinity for PtdIns(3,4,5)P3 in vitro, we wanted to examine whether this interaction occurs also in vivo. Therefore, we generated EGFP-PLD1 PX constructs. pEGFP-PLD1 PX wild type, pEGFP-PLD1 PX(R179K) or pEGFP-PLD1 PX(R179A) were expressed in NIH-3T3 cells. After 24 hours of serum starvation, we observed a diffused pattern of the wild type and both mutants in the cytosol (Fig. 2A). Interestingly, after a 5-minute treatment with PDGF, EGFP-PLD1 PX as well as Bruton's tyrosine kinase (Btk) PH domain, which specifically recognizes PtdIns(3,4,5)P3, were localized in plasma membrane. The R179K and R179A mutants, however, which have no affinity to PtdIns(3,4,5)P3 in vitro, did not change their intracellular localization in the presence of PDGF. Moreover, when cells were fractionated into cytosolic (Cyt) and membrane (Mem) fractions, only the wild-type PLD1 PX domain showed membrane localization after PDGF treatment (Fig. 2B). To further determine whether the plasma membrane localization of PLD1 PX was mediated by interaction with PtdIns(3,4,5)P3, we examined the effect of LY 294002, a PI3K-specific inhibitor. When cells were pre-treated with LY 294002, a PDGF-induced plasma membrane localization of PLD1 PX did not occur (Fig. 3A). This was further confirmed by the cell-fractionation studies (Fig. 3B). Taken together, these data show that the PLD1 PX domain can interact with PtdIns(3,4,5)P3 in vivo, resulting in its localization in the plasma membrane in NIH-3T3 cells.
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PtdIns(3,4,5)P3 activates PLD1 in vitro
We found that the PLD1 PX domain serves as a PtdIns(3,4,5)P3-binding module. Thus we investigated whether the interaction of PtdIns(3,4,5)P3 with the PLD1 PX domain plays a regulatory role in the enzymatic activity of PLD. In vitro, PLD activity was measured as described in Materials and Methods, using phosphoinositide-containing lipid vesicles as a substrate. Homogenates of HEK 293 cells transfected with wild-type PLD1, R179K PLD1 or R179A PLD1 were used as an enzyme source. As shown in Fig. 4A, PtdIns(4,5)P2, which was previously reported to stimulate PLD (Kim et al., 1998; Sciorra et al., 1999
), enhanced the activities of PLD1 wild type, R179K and R179A. Addition of ARF and GTP
S further stimulated the PtdIns(4,5)P2-induced activation of wild-type PLD1 and the two mutants R179K and R179A PLD1 (data not shown), indicating that both mutants can response to ARF, a well known activator of PLD1 (Hammond et al., 1997
). Interestingly, PtdIns(3,4,5)P3 strongly stimulated wild-type PLD1 activity when compared with PLD1(R179K) or PLD1(R179A). Moreover, as shown in Fig. 4B, PtdIns(3,4,5)P3-induced PLD1 activation occurs in a dose-dependent manner. These results indicate that PtdIns(3,4,5)P3 interacts directly with the PX domain of PLD1 and stimulates its activity in vitro.
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Discussion |
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The downstream molecular mechanisms that mediate the suggested function of PI3K in growth-factor-induced signal transduction such as cell survival, vesicle trafficking and cytoskeletal rearrangement (Downward, 1997; Fruman et al., 1998
; Martin, 1998
; Rameh and Cantley, 1999
; Toker and Cantley, 1997
) are not fully understood. To elucidate how PI3K acts, several laboratories have tried to identify PtdIns(3,4,5)P3-binding proteins (Fukui et al., 1998
; Vanhaesebroeck et al., 2001
). PDK-1 is a well known PtdIns(3,4,5)P3-binding protein that translocates to the plasma membrane after binding to PtdIns(3,4,5)P3 through its PH domain, thus regulating the metabolism and cell-survival-related roles of PI3K by phosphorylating Akt. In addition, SWAP-70, a PtdIns(3,4,5)P3-dependent guanine nucleotide exchange factor (GEF) for Rac, can regulate membrane ruffling induced by epidermal growth factor (EGF) or PDGF (Shinohara et al., 2002
). Although it was reported that the inhibition of PI3K activity results in the downregulation of PLD activity (Emoto et al., 2000
; Kozawa et al., 1997
; Standaert et al., 1996
), the mechanism involved is unknown. Our finding that the PLD1 PX domain has affinity for PtdIns(3,4,5)P3 is an important clue. It provides an explanation for the previously suggested molecular mechanism that PLD is involved in insulin-like growth factor I (IGF-I)-induced ERK activation in Chinese hamster ovary (CHO) cells (Banno et al., 2003
). Furthermore, we found that PLD1 can mediate the activation of the MAPK pathway by interacting with PtdIns(3,4,5)P3, the product of PI3K activity (Fig. 5). Taken together, we suggest that PLD1 is a novel PtdIns(3,4,5)P3-binding protein that can mediate PI3K signaling.
PtdIns(4,5)P2 has been considered to be a major regulator of PLD1 in enzymatic activity and cellular localization by binding to the PH domain of PLD1 (Hodgkin et al., 2000). Although PtdIns(3,4,5)P3 has also been reported to activate PLD1 in vitro, the mechanism involved is unclear. For example, PtdIns(3,4,5)P3 activated PLD1, purified from insect (Sf9) cells, in the presence of ARF (Hammond et al., 1997
; Min et al., 1998
) or Rac1 (Hodgkin et al., 2000
). Under our assay conditions, we found that PtdIns(4,5)P2 and PtdIns(3,4,5)P3 stimulated the activity of wild-type PLD1 almost equally when GTP
S and ARF were added (data not shown), which is in agreement with Min et al. (Min et al., 1998
). In the absence of ARF, however, activation of PLD1 by PtdIns(3,4,5)P3 was about 1.3-fold stronger than that by PtdIns(4,5)P2 (Fig. 4). Differences between the activation potentials of PtdIns(4,5)P2 in the presence or absence of ARF might be due to its abilities to directly bind to ARF (Randazzo, 1997
) and to stimulate GDP dissociation and GTP binding of ARF (Terui et al., 1994
). In conclusion, we suggest that the PX domain of PLD1 plays a role in the PtdIns(3,4,5)P3-dependent activation of PLD1 in vitro. We also demonstrate for the first time that PLD1 can be activated by PtdIns(3,4,5)P3 through direct interaction in cells (Figs 5 and 6).
In the present study, we observed that the activation of PLD1 in vitro and in vivo depends on the interaction of PLD1 PX with PtdIns(3,4,5)P3. Another example of the PX-phosphoinositide-interaction-dependent enzymatic activation was reported for cytokine-independent survival kinase (CISK) (Virbasius et al., 2001). This study suggested that binding of the CISK PX domain to PtdIns(3)P is required for its localization to endosomes and for the activation of CISK protein kinase by IGF-I or EGF. These results suggest a new feature of the PX domains not only for the translocation but also for the activation of PX-domain-containing proteins. Furthermore, in addition to its phosphoinositide-binding pocket, PLD1 PX has a phosphorylation site for protein kinase C (PKC) and can thus be phosphorylated, which enables PLD1 to be activated upon agonist stimulation (Kim et al., 2000
). Therefore, the PX domain of PLD1 is probably a center for fine-tuning and modulating enzymatic activity and localization of PLD1.
An NMR structural study of the p47phox PX domain showed that, binding of the SH3 domain to the PxxP motif caused a shift in the NMR signals of residues within its phosphoinositide-binding pocket (Hiroaki et al., 2001), and that the lipid binding also causes a shift of residues within the PxxP motif (Cheever et al., 2001
). This suggests that the binding properties of these two distinct motifs (the phosphoinositide-binding pocket and the PxxP motif) in the PX domain are allosterically regulated by each other. Recently, we reported that the PX domains of PLD interact with the SH3 domain of PLC
1 through their PxxP motifs, and that this interaction is crucial for EGF-induced PLC
1 activation and intracellular Ca2+ mobilization (Jang et al., 2003
). Taken together, the PLD PX domains might be multiple-binding modules and might have multifunctionality in order to coordinate signaling from receptors. It is not clear, however, whether protein-binding to the PLD1 PX domain alters the nature of the lipid-PX interaction or vice versa. So it would be interesting to characterize the affinity and the activity profiles of the PLD1 PX domain by using a combination of binding proteins and PtdIns(3,4,5)P3.
PDGF stimulates a number of cellular responses following its binding to the specific cell surface receptor and the activation of intrinsic tyrosine kinase (Ullrich and Schlessinger, 1990; Williams, 1989). Although the main upstream signals of PDFG-induced PLD activation have been ascribed to the ARF, Rho (Shome et al., 1998
), Ral, PKC and PLC
(Lee et al., 1994
; Voss et al., 1999
; Yeo et al., 1994
) pathways, no direct evidence concerning the isotype-specific activation mechanism of PLD1 by PDGF has been available. In this study, we identified PI3K as a novel signaling molecule that specifically activates PLD1 but not PLD2 upon PDGF stimulation (Fig. 6). Thus, PDGF-induced PLD1 activation can be mediated by PI3K as well as SMGs and by the PLC
-PKC pathway for a fine-tuned regulation in cells.
PLD1 localizes in diverse subcellular membrane structures, including the endoplasmic reticulum (ER), Golgi complex, endosomes, lysosomes and in the plasma membrane (Brown et al., 1998; Jones et al., 1999
; Kim et al., 1999
; Roth et al., 1999
; Toda et al., 1999
). In this study, we found that PtdIns(3,4,5)P3 binds to the PX domain of PLD1 and induces its localization in plasma membrane. In case of wild-type PLD1, regulation of localization is performed by complex mechanisms. Hodgkin et al. reported that the deletion mutant of PLD1 (
PH-PLD1), which lacked the PH domain, showed a punctate distribution in IIC9 cells (Hodgkin et al., 2000
). In addition, we previously reported that palmitoylation is important for the localization of PLD1 in caveolin-enriched membranes (CEM) (Han et al., 2002
). Thus it is thought that the determination of PLD1 localization is achieved by the coordinated effect of lipid modification, PX-PI(3,4,5)P3-binding, interaction of PH domain and polybasic motif-PI(4,5)P2, as well as, presumably, by association with binding proteins in the membrane. Furthermore, considering that the full-length PLD1(R179K) mutant, which cannot bind to PI(3,4,5)P3, still showed a localization pattern similar to the one of wild type PLD1 (data now shown), we speculate that the combination of palmitoylation and PI(4,5)P2-binding is a major determinant for PLD1 to localize in the plasma membrane. After that, binding of PLD1 to PX-PI(3,4,5)P3 occurs, thereby generating additional linkage to the plasma membrane. Nevertheless, there remains a discrepancy in terms of the localization of full-length PLD1. Recently, Du et al. showed that the PX domain of PLD1 participates in the recycling of PLD1 into perinuclear vesicles after PMA stimulation of COS-7 cells (Du et al., 2003
), thereby identifying PLD1 PX as a recycling regulatory domain. In NIH-3T3 cells, however, we observed no dramatic effects of LY 294002 in the localization of wild-type PLD1 (data not shown). To clarify this issue, extensive studies concerning cell type specificity, experimental conditions, mutant comparisons and lipid modifications will be necessary.
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Acknowledgments |
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References |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Ago, T., Takeya, R., Hiroaki, H., Kuribayashi, F., Ito, T., Kohda, D. and Sumimoto, H. (2001). The PX domain as a novel phosphoinositide-binding module. Biochem. Biophys. Res. Commun. 287, 733-738.[CrossRef][Medline]
Auger, K. R., Serunian, L. A., Soltoff, S. P., Libby, P. and Cantley, L. C. (1989). PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell 57, 167-175.[CrossRef][Medline]
Bae, Y. S., Sung, J. Y., Kim, O. S., Kim, Y. J., Hur. K. C., Kazlauskas, A. and Rhee, S. G. (2000). Platelet-derived growth actor-induced H2O2 production requires the activation of phosphatidylinositol 3-kinase. J. Biol. Chem. 275, 10527-10531.
Banno, Y., Takuwa, Y., Yamada, M., Takuwa, N., Ohguchi, K., Hara, A. and Nozawa, Y. (2003). Involvement of phospholipase D in insulin-like growth factor-I-induced activation of extracellular signal-regulated kinase, but not phosphoinositide 3-kinase or Akt, in Chinese hamster ovary cells. Biochem. J. 369, 363-368.[CrossRef][Medline]
Brown, F. D., Thompson, N., Saqib, K. M., Clark, J. M., Powner, D., Thompson, N. T., Solari, R. and Wakelam, M. J. (1998). Phospholipase D1 localizes to secretory granules and lysosomes and is plasma-membrane translocated on cellular stimulation. Curr. Biol. 8, 835-838.[CrossRef][Medline]
Cheever, M. L., Sato, T. K., de Beer, T., Kutateladze, T. G., Emr, S. D. and Overduin, M. (2001). Phox domain interaction with PtdIns(3)P targets the Vam7 t-SNARE to vacuole membranes. Nat. Cell Biol. 3, 613-618.[CrossRef][Medline]
Cross, M. J., Roberts, S., Ridley, A. J., Hodgkin, M. N., Stewart, A., Claesson-Welsh, L. and Wakelam, M. J. O. (1996). Stimulation of actin stress fibre formation mediated by activation of phospholipase D. Curr. Biol. 6, 588-597.[CrossRef][Medline]
Currie, R. A., Walker, K. S., Gray, A., Deak, M., Casamayor, A., Downes, C. P., Cohen, P., Alessi, D. R. and Lucocq, J. (1999). Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. Biochem. J. 337, 575-583.[CrossRef][Medline]
De Camilli, P., Emr, S. D., McPherson, P. S. and Novick, P. (1996). Phosphoinositides as regulators in membrane traffic. Science 271, 1533-1539.[Abstract]
Downward, J. (1997). Role of phosphoinositide-3-OH kinase in Ras signaling. Adv. Second Mess. Phosphoprot. Res. 31, 1-10.
Du, G., Altshuller, Y. M., Vitale, N., Huang, P., Chasserot-Golaz, S., Morris, A. J., Bader, M. F. and Frohman, M. A. (2003). Regulation of phospholipase D1 subcellular cycling through coordination of multiple membrane association motifs. J. Cell Biol. 162, 305-315.
Ellson, C. D., Gobert-Gosse, S., Anderson, K. E., Davidson, K., Erdjument-Bromage, H., Tempst, P., Thuring, J. W., Cooper, M. A., Lim, Z. Y., Holmes, A. B. et al. (2001). PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40(phox). Nat. Cell Biol. 3, 679-682.[CrossRef][Medline]
Emoto, M., Klarlund, J. K., Waters, S. B., Hu, V., Buxton, J. M., Chawla, A. and Czech, M. P. (2000). A role for phospholipase D in GLUT4 glucose transporter translocation. J. Biol. Chem. 275, 7144-7151.
Frohman, M. A. and Morris, A. J. (1999). Phospholipase D structure and regulation. Chem. Phys. Lipids 98, 127-140.[CrossRef][Medline]
Frohman, M. A., Sung, T.-C. and Morris, A. J. (1999). Mammalian phospholipase D structure and regulation. Biochim. Biophys. Acta 1439, 175-186.[Medline]
Fruman, D. A., Meyers, R. E. and Cantley, L. C. (1998). Phosphoinositide kinases. Annu. Rev. Biochem. 67, 481-507.[CrossRef][Medline]
Fruman, D. A., Rameh, L. E. and Cantley, L. C. (1999). Phosphoinositide binding domains: embracing 3-phosphate. Cell 97, 817-820.[CrossRef][Medline]
Fukui, Y., Ihara, S. and Nagata, S. (1998). Downstream of phosphatidylinositol-3 kinase, a multifunctional signaling molecule, and its regulation in cell responses. J. Biochem. 124, 1-7.[Abstract]
Hammond, S. M., Jenco, J. M., Nakashima, S., Cadwallader, K., Gu, Q., Cook, S., Nozawa, Y., Prestwich, G. D., Frohman, M. A. and Morris, A. J. (1997). Characterization of two alternately spliced forms of phospholipase D1. Activation of the purified enzymes by phosphatidylinositol 4,5-bisphosphate, ADP-ribosylation factor, and Rho family monomeric GTP-binding proteins and protein kinase C-alpha. J. Biol. Chem. 272, 3860-3868.
Han, J. M., Kim, Y., Lee, J. S., Lee, C. S., Lee, B. D., Ohba, M., Kuroki, T., Suh, P. G. and Ryu, S. H. (2002). Localization of phospholipase D1 to caveolin-enriched membrane via palmitoylation: implications for epidermal growth factor signaling. Mol. Biol. Cell 13, 3976-3988.
Hiroaki, H., Ago, T., Ito, T., Sumimoto, H. and Kohda, D. (2001). Solution structure of the PX domain, a target of the SH3 domain. Nat. Struct. Biol. 8, 526-530.[CrossRef][Medline]
Ho, S. N., Hunt, H. D., Horton, R. M., Pullen, J. K. and Pease, L. R. (1989). Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene 77, 51-59.[CrossRef][Medline]
Hodgkin, M. N., Masson, M. R., Powner, D. J., Saqib, K. M., Ponting, C. P. and Wakelam, M. J. O. (2000). Phospholipase D regulation and localisation is dependent upon a phosphatidylinositol 4,5-bisphosphate-specific PH domain. Curr. Biol. 10, 43-46.[CrossRef][Medline]
Jang, I. H., Lee, S., Park, J. B., Kim, J. H., Lee, C. S., Hur, E. M., Kim, I. S., Kim, K. T., Yagisawa, H., Suh, P. G. et al. (2003). The direct interaction of phospholipase C-gamma 1 with phospholipase D2 is important for epidermal growth factor signaling. J. Biol. Chem. 278, 18184-18190.
Jones, D., Morgan, C. and Cockcroft, S. (1999). Phospholipase D and membrane traffic. Potential roles in regulated exocytosis, membrane delivery and vesicle budding. Biochim. Biophys. Acta 1439, 229-244.[Medline]
Kanai, F., Liu, H., Field, S. J., Akbary, H., Matsuo, T., Brown, G. E., Cantley, L. C. and Yaffe, M. B. (2001). The PX domains of p47phox and p40phox bind to lipid products of PI(3)K. Nat. Cell Biol. 3, 675-678.[CrossRef][Medline]
Kay, B. K., Williamson, M. P. and Sudol, M. (2000). The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains. FASEB J. 14, 231-241.
Kim, J. H., Lee, S. D., Han, J. M., Lee, T. G., Kim, Y., Park, J. B., Lambeth, J. D., Suh, P. G. and Ryu, S. H. (1998). Activation of phospholipase D1 by direct interaction with ADP-ribosylation factor 1 and RalA. FEBS Lett. 430, 231-235.[CrossRef][Medline]
Kim, J. H., Han, J. M., Lee, S., Kim, Y., Lee, T. G., Park, J. B., Lee, S. D., Suh, P. G. and Ryu, S. H. (1999). Phospholipase D1 in caveolae: regulation by protein kinase Calpha and caveolin-1. Biochemistry 38, 3763-3769.[CrossRef][Medline]
Kim, J. H., Kim, J. H., Ohba, M., Suh, P. G. and Ryu, S.H. (2005). Novel functions of the phospholipase D2-Phox homology domain in protein kinase Czeta activation. Mol. Cell. Biol. 25, 3194-3208.
Kim, Y., Han, J. M., Han, B. R., Lee, K. A., Kim, J. H., Lee, B. D., Jang, I. H., Suh, P. G. and Ryu, S. H. (2000). Phospholipase D1 is phosphorylated and activated by protein kinase C in caveolin-enriched microdomains within the plasma membrane. J. Biol. Chem. 275, 13621-13627.
Kozawa, O., Blume-Jensen, P., Heldin, C. H. and Ronnstrand, L. (1997). Involvement of phosphatidylinositol 3'-kinase in stem-cell-factor-induced phospholipase D activation and arachidonic acid release. Eur. J. Biochem. 248, 149-155.[Abstract]
Lee, T. G., Park, J. B., Lee, S. D., Hong, S., Kim, J. H., Kim, Y., Yi, K. S., Bae, S., Hannun, Y. A., Obeid, L. M. et al. (1997). Phorbol myristate acetate-dependent association of protein kinase C alpha with phospholipase D1 in intact cells. Biochim. Biophys. Acta 1347, 199-204.[Medline]
Lee, Y. H., Kim, H. S., Pai, J. K., Ryu, S. H. and Suh, P. G. (1994). Activation of phospholipase D induced by platelet-derived growth factor is dependent upon the level of phospholipase C-gamma 1. J. Biol. Chem. 269, 26842-26847.
Martin, T. F. (1998). Phosphoinositide lipids as signaling molecules: common themes for signal transduction, cytoskeletal regulation and membrane trafficking. Annu. Rev. Cell Dev. Biol. 14, 231-264.[CrossRef][Medline]
Min, D. S., Park, S.-K. and Exton, J. H. (1998). Characterization of a rat brain phospholipase D isozyme. J. Biol. Chem. 273, 7044-7051.
Odorizzi, G., Babst, M. and Emr, S. D. (2000). Phosphoinositide signaling and the regulation of membrane trafficking in yeast. Trends Biochem. Sci. 25, 229-235.[CrossRef][Medline]
Ponting, C. P. (1996). Novel domains in NADPH oxidase subunits, sorting nexins, and PtdIns 3-kinases: binding partners of SH3 domains? Protein Sci. 5, 2353-2357.
Rameh, L. E. and Cantley, L. C. (1999). The role of phosphoinositide 3-kinase lipid products in cell function. J. Biol. Chem. 274, 8347-8350.
Randazzo, P. A. (1997). Functional interaction of ADP-ribosylation factor 1 with phosphatidylinositol 4,5-bisphosphate. J. Biol. Chem. 272, 7688-7692.
Rizzo, M. A., Shome, K., Vasudevan, C., Stolz, D. B., Sung, T.-C., Frohman, M. A., Watkins, S. C. and Romero, G. (1999). Phospholipase D and its product, phosphatidic acid, mediate agonist-dependent Raf-1 translocation to the plasma membrane and the activation of the mitogen-activated protein kinase pathway. J. Biol. Chem. 274, 1131-1139.
Rizzo, M. A., Shome, K., Watkins, S. C. and Romero, G. (2000). The recruitment of Raf-1 to membranes is mediated by direct interaction with phosphatidic acid and is independent of association with Ras. J. Biol. Chem. 275, 23911-23918.
Roth, M. G., Bi, K., Ktistakis, N. T. and Yu, S. (1999). Phospholipase D as an effector for ADP-ribosylation factor in the regulation of vesicular traffic. Chem. Phys. Lipids 98, 141-152.[CrossRef][Medline]
Sciorra, V. A., Rudge, S. A., Prestwich, G. D., Frohman, M. A., Engebrecht, J. and Morris, A. J. (1999). Identification of a phosphoinositide binding motif that mediates activation of mammalian and yeast phospholipase D isoenzymes. EMBO J. 18, 5911-5921.
Scott, P. H., Brunn, G. J., Kohn, A. D., Roth, R. A. and Lawrence, J. C., Jr (1998). Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc. Natl. Acad. Sci. USA 95, 7772-7777.
Shinohara, M., Terada, Y., Iwamatsu, A., Shinohara, A., Mochizuki, N., Higuchi, M., Gotoh, Y., Ihara, S., Nagata, S., Itoh, H. et al. (2002). SWAP-70 is a guanine-nucleotide-exchange factor that mediates signalling of membrane ruffling. Nature 416, 759-763.[CrossRef][Medline]
Shome, K., Nie, Y. and Romero, G. (1998). ADP-ribosylation factor proteins mediate agonist-induced activation of phospholipase D. J. Biol. Chem. 273, 30836-30841.
Standaert, M. L., Avignon, A., Yamada, K., Bandyopadhyay, G. and Farese, R. V. (1996). The phosphatidylinositol 3-kinase inhibitor, wortmannin, inhibits insulin-induced activation of phosphatidylcholine hydrolysis and associated protein kinase C translocation in rat adipocytes. Biochem. J. 313, 1039-1046.[Medline]
Stephens, L., Anderson, K., Stokoe, D., Erdjument-Bromage, H., Painter, G. F., Holmes, A. B., Gaffney, P. R., Reese, C. B., McCormick, F., Tempst, P. et al. (1998). Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 279, 710-714.
Stokoe, D., Stephens, L. R., Copeland, T., Gaffney, P. R., Reese, C. B., Painter, G. F., Holmes, A. B., McCormick, F. and Hawkins, P. T. (1997). Dual role of phosphatidylinositol 3,4,5-trisphosphate in the activation of protein kinase B. Science 277, 567-570.
Terui, T., Kahn, R. A. and Randazzo, P. A. (1994). Effects of acid phospholipids on nucleotide exchange properties of ADP-ribosylation factor 1. Evidence for specific interaction with phosphatidylinositol 4,5-bisphosphate. J. Biol. Chem. 269, 28130-28135.
Toda, K., Nogami, M., Murakami, K., Kanaho, Y. and Nakayama, K. (1999). Colocalization of phospholipase D1 and GTP-binding-defective mutant of ADP-ribosylation factor 6 to endosomes and lysosomes. FEBS Lett. 442, 221-225.[CrossRef][Medline]
Toker, A. and Cantley, L. C. (1997). Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 387, 673-676.[CrossRef][Medline]
Ulrich, A. and Schlessinger, J. (1990). Signal transduction by receptors with tyrosine kinase activity. Cell 61, 203-212.[CrossRef][Medline]
Valius, M. and Kazlauskas, A. (1993). Phospholipase C-gamma 1 and phosphatidylinositol 3 kinase are the downstream mediators of the PDGF receptor's mitogenic signal. Cell 73, 321-334.[CrossRef][Medline]
Vanhaesebroeck, B., Leevers, S. J., Khatereh, A., Timms, J., Katso, R., Driscoll, P. C., Woscholski, R., Parker, P. J. and Waterfield, M. D. (2001). Synthesis and function of 3-phosphorylated inositol lipids. Annu. Rev. Biochem. 70, 535-602.[CrossRef][Medline]
Virbasius, J. V., Song, X., Pomerleau, D. P., Zhan, Y., Zhou, G. W. and Czech, M. P. (2001). Activation of the Akt-related cytokine-independent survival kinase requires interaction of its phox domain with endosomal phosphatidylinositol 3-phosphate. Proc. Natl. Acad. Sci. USA 98, 12908-12913.
Voss, M., Weernink, P. A., Haupenthal, S., Moller, U., Cool, R. H., Bauer, B., Camonis, J. H., Jakobs, K. H. and Schmidt, M. (1999). Phospholipase D stimulation by receptor tyrosine kinases mediated by protein kinase C and a Ras/Ral signaling cascade. J. Biol. Chem. 274, 34691-34698.
Williams, L. T. (1989). Signal transduction by the platelet-derived growth factor receptor. Science 243, 1564-1570.[Medline]
Xu, Y., Hortsman, H., Seet, L., Wong, S. H. and Hong, W. (2001). SNX3 regulates endosomal function through its PX-domain-mediated interaction with PtdIns(3)P. Nat. Cell Biol. 3, 658-666.[CrossRef][Medline]
Yamazaki, M., Zhang, Y., Watanabe, H., Yokozeki, T., Ohno, S., Kaibuchi, K., Shibata, H., Mukai, H., Ono, Y., Frohman, M. A. et al. (1999). Interaction of the small G protein RhoA with the C terminus of human phospholipase D1. J. Biol. Chem. 274, 6035-6038.
Yeo, E. J., Kazlauskas, A. and Exton, J. H. (1994). Activation of phospholipase C-gamma is necessary for stimulation of phospholipase D by platelet-derived growth factor. J. Biol. Chem. 269, 27823-27826.
Zhan, Y., Virbasius, J. V., Song, X., Pomerleau, D. P. and Zhou, G. W. (2002). The p40phox and p47phox PX domains of NADPH oxidase target cell membranes via direct and indirect recruitment by phosphoinositides. J. Biol. Chem. 277, 4512-4518.
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