Phosphatases in Cancer

Abstract The role of phosphatases in cancer is an ignored research field, mostly based on the dogma that phosphatases function as tumor suppressor genes. However, in our opinion dephosphorylation events by phosphatases can also enhance signaling in cancer. The current research was therefore focused on elucidating the role of several phosphatases in cancer, concentrating on phosphatases which have the potential to act as oncogenes rather than tumor suppressor genes, and which can have clinical implications as biomarker or future treatment target. More specifically, we investigated the role of the Low Molecular Wei

Dichotomal effect of space flight-associated microgravity on stress-activated protein kinases in innate immunity

Space flight strongly moderates human immunity but is in general well tolerated. Elucidation of the mechanisms by which zero gravity interacts with human immunity may provide clues for developing rational avenues to deal with exaggerated immune responses, e.g. as in autoimmune disease. Using two sounding rockets and one manned Soyuz launch, the influence of space flight on immunological signal transduction provoked by lipopolysaccharide (LPS) stimulation was investigated in freshly isolated peripheral blood monocytes and was compared to samples obtained from on-board centrifuge-loaded 1a'...g controls. The effect of microgravity on immunological signal transduction is highly specific, since LPS dependent Jun-N-terminal kinase activation is impaired in the 0a'...g condition, while the corresponding LPS dependent activation of p38 MAP kinase remains unaffected. Thus our results identify Jun-N-terminal kinase as a relevant target in immunity for microgravity and support using Jun-N-terminal kinase specific inhibitors for combating autoimmune disease

Land ahoy? Navigating the genomic landscape of speciation while avoiding shipwreck

If there is one certainty about speciation, it is that those who research the process are able to disagree about almost anything. Arguments have raged over how to define species, over the importance of spatial separation and, more recently, over whether peaks of differentiation in genome scans might point to barrier loci. The debate calling attention to the shortcomings of searching for ‘genomic islands’ (Noor & Bennett, 2009; Cruickshank & Hahn, 2014) has been important to clarify where we are heading before scarce research funding is blown on tortuous journeys (sensu Baird, 2017). With our review (Ravinet et al., 2017), we aimed to clarify some of the issues surrounding interpretations of genome scan data and to suggest a practical way forward in dealing with the confounding factors that might obscure the genomic signal of reproductive isolation (RI). As the commentaries in this issue show, there is clearly still room for discussion and deeper understanding, as well as a penchant for inventive and maritime themed titles. In the interest of space, we will not respond to all the points the commentaries make; instead, our aim here is to highlight, and expand a little, on some of the common themes raised

Low molecular weight protein tyrosine phosphatase (LMWPTP) upregulation mediates malignant potential in colorectal cancer

Phosphatases have long been regarded as tumor suppressors, however there is emerging evidence for a tumor initiating role for some phosphatases in several forms of cancer. Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP; acid phosphatase 1 [ACP1]) is an 18 kDa enzyme that influences the phosphorylation of signaling pathway mediators involved in cancer and is thus postulated to be a tumor-promoting enzyme, but neither unequivocal clinical evidence nor convincing mechanistic actions for a role of LMWPTP have been identified. In the present study, we show that LMWPTP expression is not only significantly increased in colorectal cancer (CRC), but also follows a step-wise increase in different levels of dysplasia. Chemical inhibition of LMWPTP significantly reduces CRC growth. Furthermore, downregulation of LMWPTP in CRC leads to a reduced migration ability in both 2D- and 3D-migration assays, and sensitizes tumor cells to the chemotherapeutic agent 5-FU. In conclusion, this study shows that LMWPTP is not only overexpressed in colorectal cancer, but it is correlated with the malignant potential of this cancer, suggesting that this phosphatase may act as a predictive biomaker of CRC stage and represents a rational novel target in the treatment of this disease.6108300831

Key considerations for measuring allelic expression on a genomic scale using high-throughput sequencing

Differences in gene expression are thought to be an important source of phenotypic diversity, so dissecting the genetic components of natural variation in gene expression is important for understanding the evolutionary mechanisms that lead to adaptation. Gene expression is a complex trait that, in diploid organisms, results from transcription of both maternal and paternal alleles. Directly measuring allelic expression rather than total gene expression offers greater insight into regulatory variation. The recent emergence of high-throughput sequencing offers an unprecedented opportunity to study allelic transcription at a genomic scale for virtually any species. By sequencing transcript pools derived from heterozygous individuals, estimates of allelic expression can be directly obtained. The statistical power of this approach is influenced by the number of transcripts sequenced and the ability to unambiguously assign individual sequence fragments to specific alleles on the basis of transcribed nucleotide polymorphisms. Here, using mathematical modelling and computer simulations, we determine the minimum sequencing depth required to accurately measure relative allelic expression and detect allelic imbalance via high-throughput sequencing under a variety of conditions. We conclude that, within a species, a minimum of 500–1000 sequencing reads per gene are needed to test for allelic imbalance, and consequently, at least five to 10 millions reads are required for studying a genome expressing 10 000 genes. Finally, using 454 sequencing, we illustrate an application of allelic expression by testing for cis -regulatory divergence between closely related Drosophila species.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79397/1/MEC_4472_sm_SupportingInformation.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/79397/2/j.1365-294X.2010.04472.x.pd

Meeting Report Europhosphatase 2015: Phosphatases as Drug Targets in Cancer

Phosphatases are key regulators of cellular signaling and as such play an important role in nearly all cellular processes governing diseases, including cancer. However, due to their highly conserved structure and highly charged and reactive catalytic site, they have been regarded as "undruggable." Fortunately, during the recent Europhosphatase meeting (Turku, Finland), it became clear that phosphatases can no longer be ignored as potential targets in cancer therapy. As reactivation of tumor-suppressor phosphatases or direct inhibition of phosphatases acting as oncogenes is becoming available, this class of enzymes can now be considered as feasible drug targets. (C) 2016 AACR

The role of protein tyrosine phosphatases in colorectal cancer

Colorectal cancer is one of the most common oncogenic diseases in the Western world. Several cancer associated cellular pathways have been identified, in which protein phosphorylation and dephosphorylation, especially on tyrosine residues, are one of most abundant regulatory mechanisms. The balance between these processes is under tight control by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Aberrant activity of oncogenic PTKs is present in a large portion of human cancers. Because of the counteracting role of PTPs on phosphorylation-based activation of signal pathways, it has long been thought that PTPs must act as tumor suppressors. This dogma is now being challenged, with recent evidence showing that dephosphorylation events induced by some PTPs may actually stimulate tumor formation. As such, PTPs might form a novel attractive target for anticancer therapy. In this review, we summarize the action of different PTPs, the consequences of their altered expression in colorectal cancer, and their potential as target for the treatment of this deadly disease