Том 11, № 1 (2011)

Microcystins are cyclic heptapeptide toxins produced by a number of genera of cyanobacteria. They are ubiquitous in bodies of water worldwide and pose significant hazard to human, plant, and animal health. Microcystins are primarily hepatotoxins known to inhibit serine-threonine phosphatases leading to the disruption of cascade of events important in the regulation and control of cellular processes. Covalent binding of microcystins with phosphatases is thought to be responsible for the cytotoxic and genotoxic effects of microcystins. In addition, microcystins can trigger oxidative stress in cells resulting in necrosis or apoptosis. Their cyclic structure and novel amino acids enhance their stability and persistence in the environment. Humans are primarily exposed to microcystins via drinking water consumption and accidental ingestion of recreational water. Recreational exposure by skin contact or inhalation to microcystins is now recognized to cause a wide range of acute illnesses which can be life-threatening. Microcystins are primarily degraded by microorganisms in the environment, while sunlight can cause the isomerization of the double bonds and hydroxylation in the presence of pigments. Attempts to utilize these organisms in sand and membrane filters to treat water contaminated with microcystins showed complete removal and detoxification. Conventional water treatment processes may not fully eliminate microcystins when there are high levels of organic compounds especially during harmful bloom events. Combination of conventional and advanced oxidation technologies can potentially remove 100% of microcystins in water even in turbid conditions. This review covers selected treatment technologies to degrade microcystins in water.

Intracellular signaling is governed by protein phosphorylation and dephosphorylation catalyzed by protein kinases and protein phosphatases, respectively. Since there is growing evidence that a variety of protein phosphatases are involved in the pathogenesis of various diseases, protein phosphatases have recently been the focus of intense research interest, not only in basic biology but also in clinical medicine. In the process of these studies, analytical methods for protein phosphatases will be of increasing importance. A major bottleneck in protein phosphatase assays is the selection and preparation of an efficient substrate for the phosphatase to be assayed. To circumvent this difficulty, a variety of protein phosphatase substrates have been devised during the development of novel assay techniques by which protein phosphatase activities can be readily detected. In this review, we focus on the methodology for detecting protein phosphatase activities, with special emphasis on in-gel protein phosphatase assays and related techniques. The utility and limitations of these methods are also discussed.

Coordinated coupling of biochemical reactions involving protein phosphorylation and dephosphorylation represents the hallmark of the intracellular signal transduction machinery. Distinct classes of enzymes known as kinases and phosphatases respectively drive these reactions. Alterations in activity of such signaling intermediates, either due to mutations in the corresponding genes or epigenetic modulation of their expression levels, is often the cause of many cancers. The role of kinases during signal transduction has been extensively investigated over the past several decades and the consensus view is that subsets of kinases form distinct cascades of signaling pathways. Further, the extensive crosstalk that exists between these cascades leads to a complex network configuration for the signaling machinery. Inhibitors of many of these kinases are now being exploited in cancer therapy. In contrast to this, regulation by cellular phosphatases has generally been considered to occur through isolated interactions between a given phosphatase and its target substrate. Emerging evidence, however, is beginning to suggest that phosphatases also inter-regulate each other and that such interactions can lead to the formation of discrete phosphatase-specific cascades. A phosphatase cascade may be defined broadly as a series of successive dephosphorylation reactions that occur within a cell and are catalyzed by phosphatases which are activated sequentially. In general, the term 'phosphatase cascade' refers to cascades that include two or more phosphatase members [1-4]. The crosstalk between such regulatory axes of phosphatase and kinase cascades provides for complex modes of regulation, with non-linear signal input/output relationships. This review discusses the implications of such phosphatase-constituted regulatory elements for both signal processing and transmission. Further, we also explore the potential that insights on the functioning of phosphatase cascades offers, for the development of new and selective strategies for cancer therapy.

The reversible phosphorylation of tyrosine residues in proteins, which is governed by the balanced action of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), is a key element of the signaling pathways that are involved in the control of cell proliferation. Deregulation of either of these key regulators leads to abnormal cell signaling, which is largely associated with human pathologies including cancer. This review focuses on recent studies on the role of the protein tyrosine phosphatase SHP-1 on cell-cycle regulation and its possible roles in tumour onset and progression. SHP-1 is a PTP with two SH2 domains that is expressed in haematopoietic cells and, moderately, in many other cell types, especially malignant epithelial cells. SHP-1 regulates cell proliferation, whether it is by controlling mitogenic pathways activated by receptors with tyrosine kinase activity, or by regulating components of the cell-cycle machinery such as CDK2, p27 and cyclin D1. Since several inhibitors targeting SHP-1 have demonstrated their value in cancer treatment, this phosphatase has been proposed as a therapeutic target for this pathology.

The protein tyrosine phosphatase family (PTP) contains a group of dual-specificity phosphatases (DUSPs) that regulate the activivity of MAP kinases (MAPKs), which are key effectors in the control of cell growth and survival in physiological and pathological processes, including cancer. These phosphatases, named as MKP-DUSPs, include the MAPK phosphatases (MKPs) as well as a group of small-size atypical DUSPs structurally and functionally related to the MKPs. MKP-DUSPs, in most of the cases, are direct inactivators of MAPKs by dephosphorylation of both the Thr and the Tyr regulatory residues at the MAPKs catalytic loop. In some other cases, MKPDUSPs regulate the activity of MAPKs indirectly, acting through upstream MAPK pathways components. The active involvement of MKP-DUSPs in oncogenesis or resistance to cancer therapies is now well documented, making the search and validation of MKP-DUSPs inhibitors a prominent area in clinical cancer research. Here, we review the current knowledge on the role of MKP-DUSPs in human cancer, the status of the preclinical development and validation of specific MKP-DUSP inhibitors, and the potential of MKP-DUSPs as targets for anti-cancer drugs.

Reversible protein tyrosine phosphorylation, catalysed by the counter-actors protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs), is a fundamentally important regulatory mechanism of proteins in living cells, controlling cell communication, proliferation, differentiation, motility, and molecular trafficking. The activities of PTPs and PTKs are derailed in several diseases such as cancer and type II diabetes, making them attractive drug targets. Developing drugs against PTKs has started a decade earlier than that on PTPs, and at present there are several molecules targeting PTKs on the market. PTPs in turn are of raising interest, with PTP1B on the lead for its effects on type II diabetes and obesity. In the search for modulators of PTP activity, high-throughput methods are important as the initial step to find suitable lead compounds for drug development. Also, high-throughput methods are very useful in elucidating the specific function of different PTPs. In this review, the different high-throughput studies performed to find inhibitors and activators of classical PTPs are discussed.

Protein tyrosine phosphatases (PTPs) are a large family of signaling enzymes playing critical role in signal transduction and regulation of cellular processes. Dysfunction of PTP activity is associated with diabetes, cancer, autoimmune disorders, and neural diseases. PTP inhibitors therefore emerged as promising therapeutic targets. Recent research indicates that besides small organic molecules, metal ions and metal complexes can also strongly inhibit PTPs both in vitro and in vivo, resulting in the increase of phosphorylation of corresponding substrates and the modulation of cellular process. Structure of metal complexes influences the potency and selectivity of PTP inhibition. Detailed studies on this subject are not only expected to yield metal-based drugs targeting individual PTPs, but also to support understanding the function of metals in organisms. This review focuses on recent advancements in this area of research.