Regulation and Functions of Protein Kinases and PhosphatasesView this Special Issue
Review Article | Open Access
Inorganic Phosphate as an Important Regulator of Phosphatases
Cellular metabolism depends on the appropriate concentration of intracellular inorganic phosphate (Pi). Pi starvation-responsive genes appear to be involved in multiple metabolic pathways, implying a complex Pi regulation system in microorganisms and plants. A group of enzymes is required for absorption and maintenance of adequate phosphate levels, which is released from phosphate esters and anhydrides. The phosphatase system is particularly suited for the study of regulatory mechanisms because phosphatase activity is easily measured using specific methods and the difference between the repressed and derepressed levels of phosphatase activity is easily detected. This paper analyzes the protein phosphatase system induced during phosphate starvation in different organisms.
Regulation of cellular processes, such as cellular differentiation, proliferation, cell death, mobility, metabolism, survival, and organization of the cytoskeleton, in response to some stimuli is fundamental to all aspects of cell life [1–4]. Protein phosphorylation is one of the most common mechanisms used to regulate these processes. Processes that are reversibly controlled by protein phosphorylation require both a protein kinase and a protein phosphatase [5–7].
Traditionally, protein kinases have been studied more intensely than protein phosphatases due to the earlier view that protein kinases confer fine regulation to protein phosphorylation, whereas protein phosphatases merely act to remove phosphate groups. Only in the last decade was it realized that protein phosphatases are also regulated by a variety of mechanisms and are of no less importance to cellular physiology than protein kinases . Protein phosphatases are able to hydrolyze phosphomonoester metabolites, releasing inorganic phosphate (Pi) from these substrates [5, 9].
Phosphorus, in the form of inorganic phosphate (Pi), is one of the most important macronutrients for all organisms [7, 10–13]. It is not only used in the biosynthesis of cellular components, such as ATP, nucleic acids, phospholipids, and proteins, but it is also involved in many metabolic pathways, including energy transfer, protein activation, and carbon and amino acid metabolic processes . Large amounts of phosphate are required for cell survival. In plants, Pi is essential for growth and development . In fungi, the Pi signal transduction pathway regulates the expression of many phosphate responsive genes that are involved in scavenging and Pi uptake from extracellular sources . In trypanosomatid parasites, Pi influences their ability to correctly grow and colonize in the invertebrate host [17, 18].
In summary, protein phosphatases and kinases are necessary for Pi homeostasis during the acquisition, storage, release, and metabolic integration of Pi [19–23]. The purpose of this paper is to summarize the regulation of phosphatases by inorganic phosphate, with an emphasis on the role of these enzymes in cell biology.
2. Feedback Control of Phosphatases by Inorganic Phosphate: The PHO Pathway
Saccharomyces cerevisiae has several phosphatases with different specificities, cellular location, and permeases used in Pi uptake. The set of genes responsible for these activities are coordinately repressed by the Pi concentration in the growth medium . The cell acquisition, storage, release, and metabolic integration of Pi requires the participation of many essential enzymes such as extracellular acid phosphatases (APases), phosphodiesterases, Pi transporters, polyphosphate kinases, alkaline phosphatases (ALPases), and endopolyphosphatases [19–21]. The activities of these enzymes are intrinsically linked to Pi homeostasis, and they are subjected to regulation via the Pi signal transduction pathway (PHO) in response to varying Pi levels [21, 24].
In one current model for PHO regulation, the positive regulator (or positive factor) Pho4p, encoded by the PH04 gene, is indispensable for transcriptional activation of PHO genes by its activity and location. In high Pi medium, a cyclin-dependent kinase (CDK) complex consisting of Pho80p and Pho85p inhibits Pho4p function by hyperphosphorylation. Hyperphosphorylated Pho4p remains in the cytoplasm and is unable to activate the transcription of the PHO genes [25, 26]. When the Pi concentration in the medium is sufficiently low, Pho81p inhibits the function of the Pho80p-Pho85p complex [26, 27], allowing Pho4p to relocate to the nucleus and activate transcription of the PHO genes [20, 25]. These genes encode for the high-affinity transporters Pho84p and Pho89p; secreted acid phosphatases Pho5p, Pho11p, and Pho12p; other related proteins that increase Pi recovery from extracellular sources [24, 28].
3. The Phosphatase System in Yeast
Initially, it was observed that a several phosphatase genes are modulated by the Pi concentration in the culture medium; thus, the PHO pathway was initially characterized by differentially expressed phosphatases .
In S. cerevisiae, the transcription of genes encoding acid and alkaline phosphatases and the Pi transporter is coordinately repressed and derepressed depending on the Pi concentration in the culture medium . Most of the phosphatases synthesized under Pi limiting conditions are extracellularly located or are associated with the plasma membrane or cell wall .
The Pi-regulated phosphatase genes include PHO5 , which encodes for the major fraction of repressible acid phosphatases (rAPase; optimum pH 3-4; EC 188.8.131.52), and its isozymes PHO10 and PHO11 . These three rAPases are glycoproteins that are found in the cell wall or the periplasmic space. They are responsible for phosphate scavenging and work in conjunction with high-affinity transporters to acquire phosphate when the Pi concentration in the environment is low [24, 43]. The rAPase encoded by the PHO5 gene is glycosylated during secretion across the membrane and is localized in the periplasmic space . Pho5p is responsible for >90% of APase activity .
Because the PHO5 gene product constitutes the bulk of the acid phosphatases, PHO5 regulation is key to cellular phosphate homeostasis. Transcriptional activators, Pho4p and Pho2p, are required to generate the active chromatin structure in the PHO5 promoter and stimulate transcription. Pho80p-Pho85p is a cyclin/cyclin-dependent kinase complex that phosphorylates Pho4p at multiple sites to negatively regulate Pho4p function . Huang and O’Shea  carried out a high-throughput, quantitative, enzymatic screen of a yeast deletion collection, searching for novel mutants defective in PHO5 expression. Among the constitutive mutants, the pho80 and pho85 strains showed the most elevated levels of Pho5 phosphatase activity and PHO5 mRNA under high-phosphate conditions, consistent with their central role in the PHO pathway. Complete loss of the high kinase activity (Pho80p-Pho85) results in full activation of the Pho4 transcription factor, leading to full PHO5 expression.
Another important class of phosphatases in S. cerevisiae is the alkaline phosphatases (ALPase; optimum pH 8; EC 184.108.40.206). PHO8  encodes for a nonspecific repressible alkaline phosphatase (rALPase). It is a vacuole-localized glycoprotein that cleaves diverse substrates to retrieve phosphate from intracellular products . Pho8p is an Mg2+/Zn2+-dependent dimeric protein, similar to the ALPase in Escherichia coli and in mammalian cells . The enzyme product of PHO13 is a monomeric protein and is specific for p-nitrophenyl phosphate (pNPP) and histidinyl phosphate. This enzyme was strongly activated by Mg2+ ions, with a pH optimum of 8.2 and a high specific activity for pNPP, with a mean value of 3.6 × 10-5 M .
4. Phosphorus Stress Modulates Acid Phosphatases in Plants
Acid phosphatases (APases) may be active against a wide array of organic phosphates present in soil. These enzymes are nonspecific orthophosphoric monoester phosphohydrolases (EC 220.127.116.11) that cleave Pi from ester linkage sites. Secreted plant phosphatases sustain 50% activity over a broad pH range (4.0–7.6), maintain 80% activity over a broad temperature range (22°C–48°C), and are stable at temperatures as high as 60°C, making them ideal candidates for active soil enzymes [48–50].
APases are abundant in Arabidopsis and are represented by at least four gene families. A recent survey of the annotated Arabidopsis genome identified sequences for 1 His APase, 4 phosphatidic APases, 10 vegetative storage protein APases, and 29 purple APases [50, 51].
In recent years, there has been considerable interest in purple APases (PAPs). Comparative analysis of the structure of PAPs from higher plants and mammals has allowed for the identification of conserved sequence and structural motifs in this type of enzyme from many eukaryotic species [51, 52].
Biochemically, plant PAPs function as homodimeric proteins with a molecular mass of ~55 kDa per monomer, whereas mammalian PAPs are typically monomeric proteins with a molecular mass of ~35 kDa [51–53]. Many PAPs are glycoproteins that are targeted to the secretory pathway . One PAP from Spirodela oligorrhiza has been found to be glycosylphosphatidylinositol anchored in the cell . Structurally, plant PAPs have two domains. The NH2-domain does not have catalytic function. The COOH-domain has the metal center and is the catalytic domain of the enzyme. Another PAP from Lupinus albus may contain a third domain, with a structure resembling that of sterol desaturases, at its carboxyl terminus . It is not known how common the latter two forms of posttranslational modification are in PAPs from other species. PAPs are metalloenzymes that have a binuclear metal ion complex in its active site. Their characteristic pink to purple color is due to a charge transfer transition by a tyrosine residue coordinating a ferric ion [52, 56]. This enzyme can hydrolyze phosphoric acid esters and anhydrides .
PAPs have been isolated from Phaseolus vulgaris (common bean) , Glycine max (soybean) , Lupinus albus (white lupin) , Lycopersicon esculentum (tomato) , Triticum aestivum (wheat) , Hordeum vulgare (barley) , Zea maize (maize) , and Oryza sativa (rice) .
The plant response to Pi starvation can be divided into two categories: the specific response and the general response. The specific responses promote efficient mobilization and acquisition of Pi from growth medium and intracellular stores. The general responses allow for long-term survival by coordinating cell metabolism with nutrient availability and growth potential [14, 62]. The implementation of these strategies requires changes in the expression profiles of hundreds of genes, as demonstrated by the transcriptome analyses of Arabidopsis thaliana (Arabidopsis) [14, 63].
During Pi starvation, plants enhance phosphatase expression as a general response [50, 63]. Phosphatase production is linked to Pi deficiency, and a positive correlation between acid phosphatase production and Pi nutrition has been proposed [64–66]. For example, plants such as lupins, which are more efficient in acquiring Pi from the soil, produce significantly more phosphatase in comparison to cereals .
Wu et al.  analyzed the regulation of protein phosphatases in Arabidopsis and found that three genes for PAP were induced by Pi starvation. In addition, the gene At1g25230 was induced more than 2-fold, showing that this gene is responsive to Pi starvation.
In the rice genome, a total of 26 putative PAP genes were identified, and Pi starvation induced the expression of 10 rice PAP genes, suggesting that these play important roles in the acclimation of rice to low Pi conditions .
In Lycopersicon esculentum (tomato), LePS2, is induced by Pi starvation . It is noted that LePS2 phosphatases represent the first cytoplasmatic phosphatases that are components of the Pi starvation response . Suspending tomato cells in Pi-starved medium led to a PAP-specific activity increase of approximately 4-fold, but the PAP-specific activity remained low and constant in cells maintained in high Pi medium. The increase of PAP activity in cells growth in Pi-starved medium demonstrates that PAP could have a role in enhancing the availability and utilization of Pi and may be pivotal for mobilizing intracellular Pi by sensing a lack of Pi in tomato [60, 66].
5. Ectophosphatases as Pi Sensors
The plasma membrane of cells may contain enzymes whose active sites face the external medium rather than the cytoplasm. The activities of these enzymes, referred to as ectoenzymes, can be measured using intact cells [17, 68–73]. Ectophosphatases and ectokinases have been detected in several microorganisms, including protozoa [69, 71, 74–78], bacteria [79–82], and fungi [83–88].
Many studies have demonstrated a role of ectophosphatases in acquiring Pi for use in the growth of various cell types [73, 74, 86, 89]. In fungi cells (Fonsecae pedrosoi), the depletion of Pi from the culture medium apparently induces the expression of different ectophosphatase activities . The cultivation of these fungi in the absence of exogenous Pi has been shown to result in the generation of fungal cells expressing an ectophosphatase activity 130-fold higher than that expressed by fungi cultivated in the presence of Pi . Trypanosomatid cells have ectophosphatases that provide Pi by hydrolyzing phosphomonoester metabolites [17, 18, 51, 60, 73, 81]. For example, in T. rangeli, a low Pi concentration in the growth medium induces the expression of a different ectophosphatase activity [17, 73], suggesting that this enzyme leads to hydrolyzes phosphorylated compounds present in the extracellular medium. This hydrolysis could contribute to the acquisition of Pi during the development of T. rangeli epimastigotes .
Under conditions of Pi limitation, fluorescent bacteria Pseudomona express a set of phosphate starvation genes [90, 91]. For example, at least 56 Pi starvation proteins are induced in the P. putida strain KT2442 , and, in the P. fluorescens strain DF57, induction of several phosphate starvation genes has been reported .
In many eukaryotes, the nucleotide pyrophosphatase/phosphodiesterase (E-NPP) family of proteins is directly responsible for phosphate hydrolysis from extracellular nucleotides. NPP1 to −3 are found in nearly all human tissue types, and these enzymes contain an alkaline ectonucleotide pyrophosphatase/phosphodiesterase type 1 domain. In S. cerevisiae, NPP1 and NPP2 are upregulated via Pi-regulated transcription .
6. Concluding Remarks
Pi is a compound that is growth limiting in various organisms when its availability is low in many ecosystems . The induction of phosphatase activity in response to Pi starvation is a common phenomenon among organisms acquiring Pi from the environment. These enzymes are able to hydrolyze phosphorylated substrates to supply a source of Pi during a shortage of nutrients. In Saccharomyces cerevisiae, the Pi starvation signal triggers increased production of at least four types of phosphatases: (1) the acid phosphatases Pho5, Pho11, and Pho12, which are localized in periplasmic space; (2) the alkaline phosphatase Pho8, which is localized in the vacuole; (3) the glycerol phosphatase Hor2; (4) the putative polyphosphatase Phm5, which is localized in the vacuole. All of these enzymes can contribute to increased levels of free Pi . However, other functions could be attributed to these enzymes.
Del Pozo et al.  purified an acid phosphatase, AtACP5, that is induced by Pi starvation in Arabidopsis thaliana. This enzyme presents two activities, hydrolysis of phosphorylated substrates and peroxide formation. The phosphatase activity probably reflects a role in Pi mobilization; the peroxidation activity suggests that AtACP5 could also play a role in the metabolism of reactive oxygen species .
Taken together, Pi starvation-induced phosphatases play a role in an organism’s adaptation to stress, though other roles can be found.
The authors acknowledge the financial support given by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ). C. F. Dick and A. L. A. Dos-Santos contributed equally to this work.
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