Regulation of phospholipase D by protein kinase C

ELSEVIER

Chemistry and Physics of Lipids 80 (1996) 81 102

Review

Chemistry and Physics of LIPID$

article

Regulation of phospholipase D by protein kinase C Z. Kiss* The Hormel Institute, University of Minnesota, 801 16th Ave., NE, Austin, MN 55912. USA

Abstract

In nearly all mammalian cells and tissues examined, protein kinase C (PKC) has been shown to serve as a major regulator of a phosphatidylcholine-specific phospholipase D (PLD) activity. At least 12 distinct isoforms of PKC have been described so tar; of these enzymes only the e- and fl-isoforms were found to regulate PLD activity. While the mechanism of this regulation has remained unknown, available evidence suggests that both phosphorylating and non-phosphorylating mechanisms may be involved. A phosphatidylcholine-specific PLD activity was recently purified from pig lung, but its possible regulation by PKC has not been reported yet. Several cell types and tissues appear to express additional forms of PLD which can hydrolyze either phosphatidylethanolamine or phosphatidylinositol. It has also been reported that at least one form of PLD can be activated by oncogenes, but not by PKC activators. Similar to activated PKC, some of the primary and secondary products of PLD-mediated phospholipid hydrolysis, including phosphatidic acid, 1,2-diacylglycerol, choline phosphate and ethanolamine, also exhibit mitogenic/co-mitogenic effects in cultured cells. Furthermore, both the PLD and PKC systems have been implicated in the regulation of vesicle transport and exocytosis. Recently the PLD enzyme has been cloned and the tools of molecular biology to study its biological roles will soon be available. Using specific inhibitors of growth regulating signals and vesicle transport, so far no convincing evidence has been reported to support the role of PLD in the mediation of any of the above cellular effects of activated PKC. Kcg'words': Phospholipase D: Protein kinase C; Phosphatidylcholine: Phosphatidylethanolamine: Cell growth; Exo-

cytosis

1. Introduction

Abhret&tions: PKC, protein kinase C; PLD~ phospholipase D: PtdCho, phosphatidylcholine; PtdEtn, phosphatidylethanolamine; PIP2, phosphatidylinositol 4,5-bisphosphate; PMA, phorbol 12-myristate 13-acetate; 1,2-DAG, 1,2-diacylglycerol; PDGF, platelet-derived growth factor; EGF, epidermal growth factor: FGF, fibroblast growth factor. * Corresponding author, Tel.: + 1 (507) 437-9645, Fax: + 1 (507) 437-9606.

M e m b e r s o f the protein kinase C (PKC) family are i m p o r t a n t regulators o f m a n y cellular events [1 6]. The t u m o r p r o m o t i n g effects o f p h o r b o l 12-myristate 13-acetate ( P M A ) and several other p h o r b o l and n o n - p h o r b o l t u m o r promoters are most p r o b a b l y mediated by activated P K C [1,3]. In addition, P K C activators or overexpressed P K C isozymes usually exert m a r k e d effects, either

0009-3084/96/$15.00 ~~ 1996 Elsevier Science Ireland Ltd. All rights reserved Pll $0009- 3084(96)02547-9

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Z. Kiss / Chemistry and Physics o[' Lipids 80 (1996) 81 102

stimulatory or inhibitory, on mitogenesis [7 15]. While the PKC system clearly has a pivotal role in signal transduction pathways regulating the above cellular events, the mechanism(s) of these actions is(are) far from clear. Phospholipase D (PLD) is another potentially important regulatory enzyme which produces an array of mitogenic and co-mitogenic compounds. For this reason, regulation of PLD by PKC has generated great interest in recent years. The two major issues which will be dealt with here are how the PLD system is regulated by PKC, and what is the possible role of products of PLD-mediated phospholipid hydrolysis in the mediation of physiological effects of activated PKC? While several previous reviews on PLD regulation touched upon these issues [16-21], it appeared useful to summarize most recent developments specifically relating to the interactions between the PKC and PLD system.

2. The PKC system

The PKC enzyme family consists of at least 12 distinct protein kinases, each phosphorylating serine/threonine residues on specific substrate proteins. These enzymes can be divided into three subgroups based on structural properties and cofactor requirements. The conventional (or classical) isozymes (e, ill, flII, and 7) require for their activity phosphatidylserine and are stimulated by both Ca 2 + and diacylglycerol (1,2-DAG)/phorbol esters [22-26]; the novel isozymes (& e, r/, 0, and #) also require phosphatidylserine and bind 1,2DAG, but they lack the C2 domain and, thus, do not bind Ca 2 + [27-34]; and, the atypical isozymes (~, 2, and t) neither bind 1,2-DAG/phorbol esters nor are stimulated by C a 2 + [27,35,36]. In addition to their differential regulation, the PKC isozymes also exhibit discrete tissue specific expression and subcellular distribution [37-39]. This diversity in the PKC family suggests that the different isozymes are involved in the regulation of specific cellular functions. Indeed, various PKC isozymes have been shown to differentially regulate cell differentiation [40,41], neural induction [42], the transcriptional factors AP-I, NF-AT-1, and NF-~B [43,44], and the phosphorylation of

insulin receptor [45] and lamin B [46]. An interesting property of the conventional PKC isoforms is that upon treatment of cells with 1,2-DAG-elevating agents or phorbol ester, they translocate from the cytosolic compartment to either the plasma membrane or nuclear membrane compartment, or to cytoskeletal elements [47-54]. Association of PKC isozymes with membranes, which is thought to be required for their activation, is usually reversible; dissociation of enzyme activators leads to immediate redistribution of PKC isozymes to the cytosol [55,56]. However, membrane translocation of PKC also enhances the rate of its proteolytic degradation. Accordingly, in many cases prolonged treatments with PMA have been shown to result in practically complete elimination (down-regulation) of the 1,2-DAG/phorbol ester-sensitive PKC isozymes [57-60]. Proteolytic degradation by calpain yields a catalytically permanently active truncated enzyme (protein kinase M), which no longer binds to membranes [1,3]. It has been suggested that certain responses of neutrophils to PKC activators may be mediated by this truncated enzyme [61 63]; however, a more general role of this latter form of PKC in signal transduction remains to be proven. Perhaps reflecting differential binding of PKC isozymes to membrane components, such as the 14-3-3 ( protein [64], various PKC isozymes are translocated and down-regulated at different rates upon treatments with phorbol ester or 1,2-DAGelevating agents [65 68]. Importantly, not only the activators of PKC can down-regulate PKC isozymes. For example, in C3H/10T1/2 fibroblasts chemical carcinogens were shown to selectively down-regulate PKC-e [69]. Clearly, if it is true that PKC isozymes have distinct roles in the regulation of cellular events, then selective down-regulation of these enzymes will affect specific cellular functions, perhaps including regulation of PLD activities.

3. General properties of PLD: possible existence of different forms of PLD

Although the existence of PLD in mammalian tissues has been recognized many years ago [70

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Z. KLs's ,/Chemistry and Physics q[' Lipids 80 (1996) 81 102

Growth factors -

PMA

PKC ~

\

PLD

t

\

O-

II

II

0

0

= Phospholipid substrate

+ Base

Phosphatidic acid

PtdCho

\ \ \ EtOH"

Trar~sphosphatidylation

D-

0~'-0~

P--O--El

+ ChoPine

II 0

Phosphatidylethanol

+Base = choline, ethanolamine, inositol. * Other short-chain alcohols can substitute for EtOH as substrate and PLD activator.

Fig. 1. Schematicrepresentation of regulation of PLD activities by PKC and ethanol. 75], so far the enzyme has been partially purified from rat brain [71] and to near homogeneity from pig lung [76]. The purified enzyme from pig lung microsomes has a mass of approximately 190 kDa [76], which is close to earlier estimates using a partially purified PLD preparation from brain [71]. The purified enzyme appeared to hydrolyze only phosphatidylcholine (PtdCho) [76]; this is in contrast to an earlier observation that a partially purified enzyme from brain hydrolyzed both PtdCho and phosphatidylethanolamine (PtdEtn) at comparable rates [7l]. In general agreement with many other studies (for example, [77]), the purified enzyme produced from PtdCho either phosphatidic acid or, in the presence of ethanol, phosphatidylethanol [76] (this and other properties of PLD are shown in Fig. 1). This confirms that, at least with PtdCho as substrate, a single PLD enzyme is capable of catalyzing both the hydrolytic and transphosphatidylation reaction.

Interestingly, brain PLD also produces very little phosphatidylethanol from PtdEtn [75], despite the ability of the partially purified brain enzyme to efficiently hydrolyze PtdEtn [71]. Thus, while Ptd Etn may be a relatively good substrate for the hydrolytic activity, this phospholipid may be a poor substrate for the transphosphatidylation activity of PLD. Alternatively, different purification procedures led to the isolation of different forms of PLD exhibiting distinct substrate specificity. Using partially purified PLD preparations. phosphatidylinositol 4,5-bisphosphate (PIP;:) was shown to be a strong activator of PLD activity [78,79]. In contrast, PIP 2 only slightly stimulated the activity of purified PLD from the lung [76]. Again, this would be consistent with cells expressing different isoforms of PLD, only some of them being sensitive to the stimulatory action of PIP 2. In intact phorbol ester-treated [80] or growth factor-treated [81] NIH 3T3 fibroblasts, a PtdEtn-

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Z. Kiss/Chemistry and Physics qf Lipids 80 (1996) 81 102

hydrolyzing PLD activity was also identified on the basis of formation of [32p]phosphatidic acid from 32p-labeled PtdEtn. Similarly, PtdEtn- and phosphatidylinositol-hydrolyzing PLD activities have been described in several other cell lines [82-95]. Thus, it seems safe to conclude that in response to PKC activators several cell types are capable of hydrolyzing other phospholipids as well, in addition to PtdCho. No reliable in vitro assay for the determination of PtdEtn-hydrolyzing PLD is available yet. Analysis of molecular species of phosphatidic acid, phosphatidylethanol, and 1,2-diacylglycerol (1,2-DAG) can also provide valuable information on the in vivo substrate of PLD, provided that these products are metabolically relatively stable. In many cases, the products of PLD-mediated phospholipid hydrolysis resembled the fatty acid composition of PtdCho [96-105], confirming other lines of evidence that in most cell types this phospholipid is a major substrate of activated PLD [16 19]. However, stimulation of human mesangial cells by lipid A [90] or interleukin-I [95] resulted in the formation of 1,2-DAG and phosphatidic acid whose fatty acid composition resembled that of PtdEtn. Whether a PLD-activated agent stimulates the hydrolysis of PtdCho or Ptd Etn may also depend on the physiological state of cells. For example, in proliferating or differentiated LA-N-1 neuronal cells, phorbol ester stimulated the hydrolysis of PtdCho or PtdEtn, respectively [105]. While the above data indicate that the PLD enzyme (or enzymes) may select a substrate according to the nature of the phospholipid polar group, it is less clear how PLD activity may depend on the fatty acid composition of substrate phospholipids. For example, Huang et al, [106] reported that in Madin-Darby canine kidney cells PKC activators selectively enhance PLD-mediated hydrolysis of ether-linked phospholipids, while a G-protein regulated PLD preferentially hydrolyzes the ester-linked subclass. In contrast, activated PLD in HeLa cells [107,108] or in synaptic membranes [109] did not effectively discriminate between the ester- and ether-linked phospholipids. Some of these observations clearly raise the possibility that cells contain different forms of

PLD, which may be differentially regulated, and may also exhibit different substrate specificity. Several major observations support this possibility. First, Wang et al. [110] reported that a variety of tissues and cell types contain two different PLD activities, a membrane-bound form acting specifically on PtdCho, and a cytoplasmic form preferentially hydrolyzing PtdEtn. Second, in a multidrug-resistant line of MCF-7 human breast carcinoma cells activated PLD specifically hydrolyzed PtdEtn [111]. Third, rat brain membranes were shown to contain oleate-independent and -dependent PLD activities, only the former enzyme being sensitive to ADP-ribosylation factors (ARF) 1, 5 and 6 [112]. Finally, membranes from rat heart were shown to contain a PLD activity which apparently specifically hydrolyzes N-acylethanolamine phospholipids, but not PtdCho or PtdEtn [113].

4. Regulation of PLD by the PKC system 4.1. Stimulation of phospholipid hydrolysis by PKC activators' in intact cells: role of PKC isozymes Activators of PKC uniquely stimulate both the synthesis and degradation of PtdCho. The first observations that phorbol ester stimulates choline release from cells were made in 1981-82 [114,115], but at that time the mechanism remained unknown. A few years later, Tettenborn and Mueller [116] and Pai et al, [117] demonstrated that phorbol ester-induced choline release was mediated by a PLD activity. Since then, numerous publications appeared describing phorbol ester-stimulated PLD activities in various cell types and tissues (reviewed in [16-18]); thus, it is clear that this phenomenon is nearly universal in animal cells. The few exceptions which have been reported include wild type MCF-7 breast carcinoma cells which hydrolyze neither PtdCho nor PtdEtn, and multi-drug resistant MCF-7 cells which hydrolyze only PtdEtn, but not PtdCho [llll. Despite the fact that PKC appears to be the major target of phorbol esters, initially the role of

Z. Kiss / Chemislry and Physics r!/ Lipids 80 (1996) 81 102

this enzyme in the regulation of PLD by phorbol ester was unclear. The reason for this was that in HL-60 granulocytes PKC inhibitors failed to prevent the effect of phorbol ester on PLD activation [118]. The first, although still indirect, evidence for the involvement of PKC was provided by Pai et al. [119], who demonstrated that overexpression of PKC-/)'I in Rat-6 fibroblasts enhances PLD activation by PKC activators. However, in many cell lines, including fibroblasts [69,120], phorbol esters are efficient activators of PLD even though they do not express PKC-/]. Clearly, other PKC isozyme(s) must also be able to regulate PLD activity. Overexpression of PKC-~ in Swiss/3T3 cells was also shown to up-regulate PLD, leading to a constitutive high level of enzyme activity [121]. Since in fibroblasts the level of PKC-~ is already high, it is unlikely to be the rate-limiting factor in the regulation of PLD. Thus, expression of PKC:< to an even higher level may not significantly affect PLD activity, and may not reveal dependence of PLD activity on this isoform. In recognition of this possibility, Balboa et al. [122] used antisense technology to 'knock out' the ~- and fl-isoforms of PKC in Madin-Darby canine kidney cells. They found that only in cells transfected with antisense PKC-~, but not with antisense PKC-/L was the effect of PMA on PLD activity inhibited [122]. However, both PKC-~ and PKC[] may have a major role in PLD regulation depending on the cell type. For example, comparison of the effects of recombinant PKC isozymes on PLD activity in neutrophil membranes revealed that in this case PKC-/)'I was a more potent activator than PKC-~, and that the ;,-, /]II-, rJ-, E-, q- or (-isoforms had either small effects (PKC-~,) or no effects at all (the remaining isoforms) [123]. On the other hand, it has been reported that stimulation of PLD by platelet-activating factor in Chinese hamster ovary cells [124] or by bradykinin in fibroblasts from Zellweger patients [125] involved PKC-~, The above studies assumed that PtdCho was the major substrate of PLD, without making specific efforts to identify PtdEtn as a possible substrate. Data on the regulation of PtdEtn hydrolysis by PKC isoforms are more limited. Specific down-

85

regulation of PKC-e by carcinogens in C3H/ 10TI/2 fibroblasts failed to diminish the effect of PMA on PtdEtn (and PtdCho) hydrolysis, indicating that this isozyme does not have a major role in the regulation of PtdEtn-hydrolyzing PLD [69]. On the other hand, in multi-drug resistant MCF-7 breast carcinoma cells, which express very high levels of PKC-:< and only very low levels of the other PKC isozymes [126], PMA specifically stimulated PtdEtn hydrolysis [111]. This would suggest that, at least in this cell line, PtdEtn hydrolysis is also regulated by PKC-~.. Presently, it is not clear why the drug resistant MCF-7 cells are not able to efficiently hydrolyze PtdCho. More recent work indicates that expression of PKC-:< in wild type MCF-7 cells results in the appearance of a PLD activity (or activities) which effectively hydrolyze(s) both PtdCho and PtdEtn (Z. Kiss, T. Chung, J.J. Mukherjee, and D.K. Ways, unpublished results). These findings not only confirm that the status of PKC-:< in cells has a major impact on the PtdCho- and PtdEtnhydrolyzing PLD activities, but also suggest that the multidrug resistant cells contain an endogenous inhibitor of PtdCho-specific PLD activity.,' expression. 4,2. Regu&tion o / PLD activity hv PKC and its activators in isolated memhrane.~" In rare instances, addition of phorbol ester to membrane preparations alone could elicit increased PLD-mediated phospholipid hydrolysis. For example, addition of PMA alone to a crude membrane fraction isolated from HL-60 human leukemic cells resulted in the hydrolysis of both PtdCho and PtdEtn [80]. In membranes derived from either Ha-ras- or v-tar-transformed NIH 3T3 cells PMA also induced the hydrolysis of PtdEtn in the concomitant presence of ATP and GTP[S] [127]. PMA had no effects in membranes derived from control NIH 3T3 cells [127]. Clearly, in the above cases all the components (including PLD, PKC, and perhaps other proteins and cofactors) required for the activation of PLD were already present in the isolated membranes. Interestingly, only membranes derived from transformed cells appeared to respond to PMA. This

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Z. Kiss / Chemist O, and Physics ~[' Lipids" 80 (1996) 81 102

suggests that tumor cell membranes may be a good choice to identify the components involved in the regulation of PLD by PKC activators. In a study by Conricode et al. [128], regulation of a PtdCho-specific PLD activity by PKC was examined in membranes from Chinese hamster lung fibroblasts by using the purified conventional PKC isoforms ~, fl, and 7, and the recombinant 6-, e- and (-isoforms. Both PKC-~ and PKC-/] (in that order) enhanced, while the other isoforms failed to modify PLD-mediated PtdCho hydrolysis. Interestingly, in these membranes stimulation of PLD activity by the PKC/PMA system did not require ATP [129], suggesting that in this specific case activation of PLD occurred by a non-phosphorylating mechanism. Since these reports, data both for and against this latter possibility have been reported. Thus, in NIH 3T3 fibroblasts, okadaic acid, a potent inhibitor of major phosphatases, had no effect on PMA-induced PtdCho hydrolysis, although it enhanced the effect of PMA on PtdCho synthesis [130]. Furthermore, in the same cell line even 75 /tM GF 109203X, a specific inhibitor of the phosphorylating activity of PKC, failed to suppress the stimulatory effect of PMA on PtdCho hydrolysis [131]. In contrast, GF 109203X was a potent inhibitor of PMA-induced PtdEtn hydrolysis [131]. In HL-60 granulocytes other inhibitors of PKC were also unable to block the stimulatory effect of PMA on PtdCho hydrolysis [118]. However, in neutrophil membranes regulation of PtdCho hydrolysis by PKC required ATP [123]. Similarly, regulation of PtdEtn hydrolysis by PMA in membranes from transformed cells also required ATP [127]. Collectively, these findings appear to indicate that regulation of the PtdCho-hydrolyzing PLD activity by PKC can occur by both phosphorylating and non-phosphorylating mechanisms, while regulation of PtdEtn hydrolysis probably involves only the former mechanism. The relative proportion of these mechanisms is likely to depend on the cell type, the composition of PtdCho substrate, and the presence of other components required for PLD activation. Clearly, the role of phosphorylating activity of PKC in the regulation of PLD activity remains an open issue for further studies.

4.3. Mediatory role of PKC in growth factor-stimulated PLD activity A number of mitogenic growth factors initiate a cascade of intracellular growth regulatory signals by stimulating the formation of the second messengers inositol-l,4,5-trisphosphate and 1,2-DAG from PIP2. While inositol-l,4,5-trisphosphate acts by elevating the cytosolic free Ca 2+ concentration, a major mechanism of I~2-DAG actions involves activation of PKC [1-3,132]. In view of the relationship between the hydrolysis of inositol lipids and activation of PKC, it would seem logical to expect that those growth factors which enhance the activity of phospholipase C will also stimulate PLD activity. In recent years numerous reports have appeared in support of this possibility. One of the most powerful activators of PLD is platelet-derived growth factor (PDGF), a potent mitogen for fibroblasts and smooth-muscle cells. The stimulatory effect of PDGF on PtdCho hydrolysis is dependent upon the presence of phospholipase C-71, and is preceded by the formation of 1,2-DAG from inositol phospholipids; in addition, down-regulation of PKC by prolonged treatment with PMA can completely block the PDGF effect [133 136]. In NIH 3T3 fibroblasts PDGF also stimulates PLD-mediated PtdEtn hydrolysis by a PKC-dependent mechanism [81]. In Swiss 3T3 cells, but not in other cell types, epidermal growth factor (EGF) was shown to stimulate PtdCho hydrolysis through the activation of PKC [137]. EGF is not known to stimulate PtdEtn hydrolysis. The stimulatory effects of bombesin on the hydrolysis of PtdCho [133,138 140] and PtdEtn [81] also can be blocked both by PKC inhibitors and through the down-regulation of the major PKC isoforms, implying that the effects of this growth factor are mediated by PKC. In addition to the above mitogens, thrombin [141], angiotensin II [142], IgE [143], vasopressin [144,145], and adenine nucleotides [146] have also been considered to stimulate PtdCho hydrolysis through sequential activation of the phospholipase C and PKC systems. However, the effects of adenine nucleotides on PtdEtn hydrolysis, which are readily detectable both in membranes from

Z. Kiss I CTwmist W and Physics ~!1'Lipi¢£ 80 (1906) 81 102

NlH 3T3 fibroblasts [86] and in intact fibroblasts [147], does not involve the PKC system. The stimulatory effect of bradykinin on PLD activity in human fibroblasts also involves a 1,2DAG-stimulated PKC system. However, in this case 1,2-DAG was shown to derive from rapid phospholipase C-mediated hydrolysis of PtdCho [148]. Stimulation of PLD activity by basic fibroblast growth factor (FGF) in endothelial cells appears to be even more peculiar. Although activation of PKC was again responsible for the growth factor effect, activation of PKC was not preceded by increased formation of 1,2-DAG from any source [149]. The mechanism by which F G F stimulates PKC activity has not been clarified yet. Phosphatidic acid, derived from PLD-mediated phospholipid hydrolysis, is usually readily metabolized to 1,2-DAG by the action of specific phosphohydrolases. Compared to the transient formation of 1,2-DAG from inositol phospholipids, 1,2-DAG formation from PtdCho and Ptd Etn in stimulated cells is more prolonged. Considering that PKC is a major cellular target of 1,2DAG, it is an interesting possibility that prolonged formation of this lipid may contribute to the activation of PKC. Several laboratories reported data, with notable exceptions, which support this possibility. In Madin-Darby canine kidney cells, :~j-adrenergic receptor agonists were shown to stimulate PKC activity by increasing 1,2-DAG formation from PtdCho but not from inositol phospholipids [150]. It remains to be seen whether activated PKC can further enhance PLD activity until this cycle is broken by desensitization of receptors. Similarly, interferon-: in HeLa cells [151] and interferon-;' in endothelial cells [152] were shown to rapidly stimulate PLD-mediated PtdCho hydrolysis followed by the activation of PKC. In several cell lines, including 1IC9 fibroblasts [153], HeLa and A431 cells [154], and normal skin fibroblasts and keratinocytes [155], EGF was not found to stimulate phospholipase-;, and inositol phospholipid hydrolysis. Instead, EGF stimulated PtdCho hydrolysis, and the resuiting 1,2-DAG induced sustained membrane translocation and activation of cytoplasmic PKC.

87

In some other cases, including IgE-stimulated RBE2H3 cells [156] and endothelin-stimulated bovine aortic smooth muscle cells [157], the stimulatory agent biphasically increased both the cellular content of 1,2-DAG and PKC activity. The first phase lasted for less than 1 rain and it was associated with the hydrolysis of inositol phospholipids, while the second phase lasted for 5 20 min and it was associated with the hydrolysis o1" PtdCho. In several other cases, a sustained phase of 1,2-DAG formation was not accompanied by the activation of PKC. For example, in GH~ cells thyrotropin-releasing hormone stimulated a transient, but not sustained, association of" cytosolic PKC with membranes, despite the ability of this hormone to exert a prolonged stimulatory effect on 1,2-DAG formation [158]. These authors [158] have noted that during hormone stimulation there was a marked shift in 1,2-DAG composition from an initially predominant tetraenoic to more saturated species. They concluded that in these cells saturated 1,2-DAG species do not activate PKC. As another example, Leach et al. [1591] reported that in y.-thrombin-stimulated IIC9 fibroblasts PKC can be activated by 1,2-DAG derived from phosphoinositides but not PtdCho hydrolysis. The most likely reason for these apparently contradictory observations is that the various growth regulatory agents can selectively activate a specific isoform of PLD, which then may preferentially hydrolyze certain substrates as determined by their fatty acid or polar group composition. As a result, lipid products (phosphatidic acid and 1,2-DAG) with different molecular composition are formed which then may perform specilic cellular functions. A good example for this possibility is provided by recent observations by Musial et al. [160] showing that in mesangial cells interleukin-l and endothelin induce the formation of distinct molecular species of 1,2-DAG. While interleukin1 stimulated the formation ot" ether-linked species from ethanolamine plasmalogens and vinyl etherlinked phospholipids, endothelin predominantly enhanced the formation of ester-linked species from PtdCho. The authors further showed that ester-linked, but not ether-linked, 1,2-DAG species can activate PKC in a cell-fl'ee assay system

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Z. Kiss / Chemistry and Physics ~l' Lipids 80 (1996) 81 102

[160]. In addition, alkenyl, acylglycerols were found to inhibit 1,2-DAG-stimulated PKC activity [160]. In view of these data, it is clearly of interest to further pursue possible differential effects of hormones, growth factors, and perhaps PKC activators on the formation of distinct 1,2DAG species. However, as a cautionary note, it should be reiterated that phorbol ester-stimulated PLD does not appear to effectively discriminate between the ester- and ether-linked phospholipids [107 109].

4.4. Interplay between the PKC system and GTP-binding proteins in the activation of PLD In some cell types PLD activation may be under dual control by the PKC system and GTPbinding (G) proteins. Furthermore, in streptolysin O-permeabilized HL-60 cells [161], in intact rabbit platelets [162] and in electropermeabilized human platelets [163], GTP[S] and PMA synergistically enhanced PLD activity. The mechanism of this synergistic interaction is not clear, but it may be due (among others) to the ability of GTP[S] to induce membrane localization of cytosolic PLD [164]. However, the physiological relevance of this phenomenon remains to be established, because maximal synergistic activation of PLD by GTP[S] and PMA typically required Ca 2 + in the micromolar range. It is known that a member of the Rho family of small molecular weight G proteins [165], most probably RhoA [166,167], regulates PLD activity. It has also been shown that in HL-60 cell membranes potentiation of PKC-mediated activation of PLD by GTP[S] is inhibited by the Rho GTPase dissociation inhibitor [167]. This strongly suggests that RhoA is one of the G proteins which can mediate the potentiating effects of guanine nucleotides on PKC-regulated PLD activity. ADP-ribosylation factors (ARF) are members of another subfamily of small G proteins which may also relate to the actions of PKC activators on the PLD system [168]. ARF, an important regulator of membrane traffic [168], has been shown to also activate PLD [169,170], particularly in the presence of RhoA [171,172] and/or a 50kDa cytosolic factor [173,174]. Other data also

indicate that while ARF can activate both the cytosolic and membrane-bound PLD activities, RhoA can activate only the latter activity [175]. It has also been shown that PLD is present in the Golgi-enriched membranes, and that its activation by ARF is prevented by brefeldin A, a drug which effectively blocks binding of ARF to Golgi membranes [176]. Since PKC activators stimulate the binding of ARF to the Golgi complex [177], one would expect that the effects of PKC activators on PLD activity are mediated, at least in part, by ARF. However, in NIH 3T3 fibroblasts, brefeldin A was found to enhance, rather than decrease, the effects of PMA on both PtdCho and PtdEtn hydrolysis (Z. Kiss, submitted for publication). This is not consistent with the possibility that PMA stimulates PLD activity on Golgi membranes by an ARF-mediated mechanism.

4.5. Tyrosine phosphorylation and regulation of PLD by PKC While tyrosine phosphorylation is almost universally involved in receptor coupling to growth factors, the possible contribution of tyrosine kinases to the regulation of PLD by PKC is somewhat controversial. In several cases (for example in ref. [178]) tyrosine kinase inhibitors failed to prevent stimulation of PLD activity by activated PKC. However, in Chinese hamster ovary cells the tyrosine protein kinase inhibitors ST-638 and genistein inhibited activation of PLD by PMA [179]. lnhibitors of tyrosine phosphorylation also inhibited PMA induction of PLD activity in permeabilized HE-60 cells [180], while in similar preparations the tyrosine phosphatase inhibitor vanadate potentiated the effect of PMA [181]. Collectively, these data suggest that PKC activators can stimulate PLD activity by both tyrosine phosphorylation-independent and -dependent pathways~ the former mechanism apparently being more general. Interestingly, activation of MAPK by PMA in insulin receptor overexpressing Chinese hamster ovary cells was also partially inhibited by a protein tyrosine kinase inhibitor [182], further indicating that certain cellular effects of PKC activators indeed involve downstream activation of a tyrosine kinase activity.

Z. Kiss / (7wmistrv and Physics of Lipi& 80 (1996) 81 102

4.6. Oxidant stress and P K C - a c t i v a t e d P L D

Mild oxidative modification of the regulatory domain of PKC by H202 was shown to initially enhance enzyme activity followed by inactivation o1"the catalytic site by further oxidation [183]. The activated enzyme is no longer dependent on Ca 2 or lipid factors [183], and is presumably insensitive to phorbol ester as well. Activation of Ca 2 +dependent PKC enzymes by oxidants, which is usually not accompanied by membrane translocatiom have been described by several other laboratories as well [184-188]. In view of the similar roles of activated forms of oxygen and PKC activators in tumor promotion [189], possible modulation of PLD activity by oxidized PKC isoforms has become an issue. Non-cytotoxic concentrations of H,O2 were shown to stimulate PtdCho hydrolysis both in endothelial cells [92] and NIH 3T3 cells [190]. However, in NIH 3T3 fibroblasts the effects of maximally effective concentrations of PMA and H~O, were additive (Fig. 2). Furthermore, downregulation of PKC by chronic PMA treatment enhanced, rather than decreased, the effect of H,O, on PtdCho hydrolysis [190]. These data

vs ~ m o

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E

N

'0

• 0

0

10

J PO

L.-~--,'t I 30

40

100

I

I

0

10

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30

40

100

PMA [ nM ]

Fig. 2. Effect of treatment of NIH 3T3 fibroblasts with increasing concentrations of PMA in the presence and the absence of I mM H20 ~ on the hydrolysis of PtdEtn and PtdCho. Preparations of suspended fibroblasts labeled with either IHC]ethanolamine (A) or [~4C]choline (B) were treated with the indicated concentrations of PMA for 40 min in the absence (e) or the presence (at) of 1 mM H202. Data are from ref. [190].

89

indicate that H 2 O 2 and PMA induce PtdCho-specific PLD activity by independent mechanisms. The stimulatory effects of H~O~ on PtdEtn hydrolysis, unlike on PtdCho hydrolysis, were blocked by chronic PMA treatment, consistent with the possible role of oxidized PKC in this H20_~ effect [190]. Also, H20, inhibited PMA-induced PtdEtn hydrolysis (Fig. 2). The superoxidegenerating xanthine/xanthine oxidase system or menadione failed to stimulate the hydrolysis of either PtdCho or PtdEtn [191]. However, these agents [191], similar to H~O~ [190]. inhibited PMA-induced hydrolysis of PtdEtn, but not PtdCho. Collectively, these data suggest that changes in the cellular oxidation state under pathological conditions may preferentially affect PKC-regulated PtdEtn hydrolysis. 4.7. S l a m s o f P K C - a c l i r a t e d P L D in tran,}/brmed cells

Tile activity of a PtdCho-hydrolyzing PLD activity has been reported to be higher in v-fps- and Ha-ras-transformed fibroblasts than in normal fibroblasts [192,193]. However, other studies either found no evidence for this possibility [194], or provided evidence that increased formation of choline phosphate (which may be an indirect marker of increased activity of PLD in transformed cells) reflected increased choline kinase activity [195]. Still another study has found that stimulation of PLD activity by oncogenic ras was the consequence of increased PKC activity [196]. The confusion is probably due to the fact that ras does not directly stimulate PLD activity [197]. Instead, a PtdCho-specific PLD apparently can be activated through its interaction with RalA, one of the effector molecules of ras [198]. Despite the inability of activated ras to induce significant changes in the cellular status of PKC-~ and other Ca 2~ -dependent PKC isozymes [199], the relative increase in PtdCho-specific PLD activity by PMA has always been lower in ras- or fps-transformed cells compared to control cells [200 202]. In contrast, stimulation of PtdEtn hydrolysis by PMA was actually up-regulated in ras-transformed N1H 3T3 fibroblasts by a mechanism which apparently involved a G protein [127].

Z. Kiss / Chemistry and Physics ol"Lipids 80 (1996) 81 102

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(b) PMA-pretreated

tiating effect o f sphingosine on P M A - i n d u c e d PtdEtn hydrolysis.

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4.9. Specific potentiating effects of alcohols on PMA-induced PtdEtn hydrolysis

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Fig. 3. Comparison of the effects of staurosporine, PMA and sphingosine on PtdEtn hydrolysis in control and PMA-pretreated NIH 3T3 fibroblasts. Fibroblasts were labeled with [~4C]ethanolamine for 48 h in the absence (A) or presence (B) of 300 nM PMA during the last 24 h of the labeling period. Prelabeled fibroblasts were further incubated for 20 min in the absence (©) or presence of 1 llM staurosporine (), 100 nM PMA ( ) or staurosporine plus PMA (11). If present, the concentration of sphingosine was 25 jiM. Data are from ref. [204], These studies have failed, so far, to yield a working hypothesis concerning the physiological role o f altered phospholipid metabolism in transformed cells.

Measurement o f the transphosphatidylation reaction as outlined in Fig. 1 is generally a reliable m a r k e r o f P L D activity. However, in N I H 3T3 fibroblasts ethanol and other alcohols were f o u n d to enhance the stimulatory effect of P M A on the hydrolysis o f PtdEtn (Fig. 4), but not P t d C h o [205]. In most cell types where P t d C h o appears to be the major substrate, this effect o f ethanol will not pose a problem. In contrast, in cells where P t d C h o and P t d E t n are equally g o o d substrates ( N I H 3T3 fibroblasts), or where P t d E t n is the m a j o r substrate (multidrug-resistant M C F - 7 cells) for P L D , measurement o f transphosphatidylase activity in the presence o f ethanol (or other alcohol) m a y lead to an overestimation o f the effects o f P K C activators. The mechanism by which ethanol acts on P t d E t n hydrolysis is presently unknown. 220 210

4.8. Specific synergistic effects of P K C activators and sphingosine on PtdEtn hydrolysis Sphingosine, an activator o f P L D on its own [86,203,204], has been shown to preferentially enhance the stimulatory effect o f P M A on P t d E t n hydrolysis [204]. As illustrated in Fig. 3, downregulation o f P K C isozymes by chronic treatment with P M A had several effects: (i) it enhanced P t d E t n hydrolysis a b o u t 2-fold, (ii) it abolished both the stimulatory effect o f P M A and the synergistic effects o f P M A and sphingosine, (iii) it also abolished the 2-fold stimulatory effect of the protein kinase inhibitor staurosporine, and (iv) it decreased the relative stimulatory effect o f sphingosine. These data raise the interesting possibility that N I H 3T3 fibroblasts express a P K C isozyme which exerts an inhibitory influence on P t d E t n hydrolysis. It remains to be seen whether inhibition o f this hypothetical inhibitory P K C isoform, or some other mechanism, accounts for the poten-

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Z. Kiss / Chemistry and Physics ~[" Lipids' 80 (1996) 8l- 102

5. Possible cellular effects of PKC-activated P L D

5.1. PKC-activated PLD and exocytosis Since an ARF-sensitive P L D is present in the Golgi membranes [176], and PKC is a regulator of both PLD activity and A R F binding to the Golgi, PKC-activated PLD may contribute to the regulation of vesicle transport and secretion. Indeed, activation of PKC has been shown to result in increased secretion in many different cell types [206-214]. However, PKC was not the only mediator of PMA-induced exocytosis in lacrimal gland [215]. Also, phorbol ester stimulation of export of vesicular stomatitis virus glycoprotein from endoplasmic reticulum involved a protein which contains the conserved C6H2 motif of regulatory domain of PKC but is different from the PKC enzymes [216]. Because of these latter observations, the role of PKC in exocytosis remains to be proven. Few circumstantial, but not direct, evidence suggests that PLD activation in neutrophils or H L-60 cells by leukotriene B4 [217], N-formylmethionyl-leucyl-phenylalanine or nucleotides [218] leads to increased secretion. Addition of PLD from Streptomyces chromofuscus to intact adult rat islets was also shown to induce secretion of insulin; this process was probably mediated by phosphatidic acid [219], However, Ca2+-induced exocytosis of the sperm acrosome did not appear to involve PLD activity [220]. Clearly, more direct evidence is needed to prove the role of PLD in vesicle transport and exocytosis. In particular, presently no data are available to support any role of PLD in PKC-activator-induced secretion.

5.2. PKC-activated PLD and rnitogenesis Nearly all mitogens which bind to cell membrane stimulate the hydrolysis of phospholipids often through the activation of PLD [16,17]. The secondary lipid product, 1,2-DAG, has long been known to modulate cell growth and differentiation through the activation of PKC. In addition, the primary lipid product, phosphatidic acid, has also been suggested to serve as a potential mitogenic signal on the basis that it was able to

91

stimulate cell proliferation in fibroblasts and several other cell types [221 225]. In support of this possibility, K o n d o et al. [226] found that PLD from Streptomyces chromoJuscus increased DNA synthesis in the presence of insulin, and Carnero and Lacal [227] reported that PLD microinjected into Xenopus oocytes mimicked the effects of ras on the activities of MAP kinase and SG kinase If. Activation of PLD has also been implicated in the mitogenic effects of endothelin-I in A10 vascular smooth muscle-derived cells [228]. On the other hand, in A7r5 vascular smooth muscle cells bacterial PLD or phosphatidic acid failed to stimulate MAP kinase activity or DNA synthesis [229]. Also, in Rat-1 cells endothelin-1 was a potent inducer of PLD activity but a poor stimulator of DNA synthesis [230]. Collectively, these data suggest that in certain cell types increased activity of PLD may lead to increased mitogenesis. It also seems clear that the mitogenic activity of PLD requires the presence of other factor(s) as well. Very little is known about the possible role of PLD in the mediation of mitogenic effects of activated PKC. In a recent paper, Kiss and T o m o n o [231] reported that in N I H 3T3 fibroblasts the PI3-kinase inhibitor wortmannin strongly inhibited the mitogenic effect of PMA, while it actually enhanced the stimulatory effect of PMA on PtdCho hydrolysis. In a more recent work, the same group found that in serum-free medium bryostatin and PMA had comparable stimulatory effects on DNA synthesis. In addition, while bryostatin was a poor activator of PLD, it actually strongly inhibited PMA-induced hydrolysis of PtdCho (Z. Kiss, submitted for publication). Collectively, these data indicate that in NIH 3T3 fibroblasts PLD does not mediate the mitogenic effects of PKC activators. Recent data indicate that not only phosphatidic acid, but also certain water-soluble products of phospholipid hydrolysis can also serve as mitogens or co-mitogens. Cuadrado et al. 11232] were the first to report that in fibroblasts choline phosphate enhanced DNA synthesis, although in their case significant effects required mmolar concentrations of this compound. Most recently, T o m o n o et al. [237] reported that in NIH 3T3 fibroblasts externally added choline phosphate

92

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Fig. 5. Concentration-dependent effects of ChoP on DNA synthesis in the absence and presence of insulin and ethanolamine in NIH 3T3 fibroblasts. Serum-starved (24 h) subconfluent fibroblasts were treated with various concentrations (0-1 mM) of ChoP for 16 h in the absence (O) or presence of 500 nM ihsulin (A), insulin plus 1 mM ethanolamine (ll), or insulin plus 5 mM ethanolamine (@). Data are from ref. [233]. was not only a mi!ogen on its own, but it also greatly enhanced the stimulatory effect of insulin on D N A synthesis (Fig. 5). Interestingly, even when choline phosphate was present at an optimal concentration (1 mM), ethanolamine (1 mM) still was able to double the combined mitogenic effects of insulin and choline phosphate (Fig. 5). Ethanolamine also enhanced the mitogenic effect of insulin in the absence of choline phosphate; this co-mitogenic effect of ethanolamine was further enhanced by 1-5 mM choline [233]. Since in N I H 3T3 fibroblasts intracellular ethanolamine is almost quantitatively phosphorylated by a kinase activity, there is reason to believe that the co-mitogenic effect of ethanolamine was mediated by ethanolamine phosphate. Although the mechanism(s) of the mitogenic and co-mitogenic effects of water-soluble products of phospholipid hydrolysis is not known, this phenomenon generates an immense interest because ethanolamine phosphate and/or choline phosphate levels are usually much higher in human tumors than in the corresponding normal tissues [234,235]. This probably reflects the ability of oncogenic ras,

which is found in many human cancers, to increase the activity/expression of choline/ethanolamine kinase activity [236-240]. In addition, chemical carcinogens also induced a very early increase in the activity of choline/ethanolamine kinase activity [241]. On the basis of these data it is certainly necessary to consider the possibility that choline phosphate and ethanolamine phosphate have specific active roles in cell growth regulation and perhaps even in carcinogenesis. While the limited data available argue against the role of these compounds in mediating the mitogenic effects of PKC activators, they still could be involved in the tumor promoting effects (not necessarily identical with the mitogenic effects) of PMA and other PKC activators.

6. Conclusion

Despite the large number of publications dealing with the interactions between the PKC and P L D systems, both the mechanism of PLD regulation and the physiological role of PKC-activated PLD remains to be clarified. However, recent success in purifying a PLD activity raises the hope that the appropriate tools of molecular biology will soon be available to permit a more straightforward study of the above questions.

Note added in proof

Most recently, H a m m o n d et al. reported [242] isolation of the first human PLD cDNA. The recombinant human PLD proved to be selective for PtdCho and it was stimulated by PIP 2 and ARF. In another new development, Singer et al. [243] reported that regulation of partially purified brain PLD by purified or recombinant PKC-~ occurred by a protein phosphorylation-independent mechanism.

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