The protein tyrosine phosphatase Pez regulates TGFβ, epithelial–mesenchymal transition, and organ development

Epithelial–mesenchymal transition (EMT), crucial during embryogenesis for new tissue and organ formation, is also considered to be a prerequisite to cancer metastasis. We report here that the protein tyrosine phosphatase Pez is expressed transiently in discrete locations in developing brain, heart, pharyngeal arches, and somites in zebrafish embryos. We also find that Pez knock-down results in defects in these organs, indicating a crucial role in organogenesis. Overexpression of Pez in epithelial MDCK cells causes EMT, with a drastic change in cell morphology and function that is accompanied by changes in gene expression typical of EMT. Transfection of Pez induced TGFβ signaling, critical in developmental EMT with a likely role also in oncogenic EMT. In zebrafish, TGFβ3 is co- expressed with Pez in a number of tissues and its expression was lost from these tissues when Pez expression was knocked down. Together, our data suggest Pez plays a crucial role in organogenesis by inducing TGFβ and EMT

Estrogen transactivates EGFR via the sphingosine 1-phosphate receptor Edg-3: the role of sphingosine kinase-1

The transactivation of enhanced growth factor receptor (EGFR) by G protein–coupled receptor (GPCR) ligands is recognized as an important signaling mechanism in the regulation of complex biological processes, such as cancer development. Estrogen (E2), which is a steroid hormone that is intimately implicated in breast cancer, has also been suggested to function via EGFR transactivation. In this study, we demonstrate that E2-induced EGFR transactivation in human breast cancer cells is driven via a novel signaling system controlled by the lipid kinase sphingosine kinase-1 (SphK1). We show that E2 stimulates SphK1 activation and the release of sphingosine 1-phosphate (S1P), by which E2 is capable of activating the S1P receptor Edg-3, resulting in the EGFR transactivation in a matrix metalloprotease–dependent manner. Thus, these findings reveal a key role for SphK1 in the coupling of the signals between three membrane-spanning events induced by E2, S1P, and EGF. They also suggest a new signal transduction model across three individual ligand-receptor systems, i.e., “criss-cross” transactivation

Judicial Review, Irrationality, and the Legitimacy of Merits-Review

The definition of the irrationality ground of judicial review recognises the constitutional principle of the separation of powers, in allowing for judicial control of the executive only very rarely. The author in a previous article in this study found that the courts, on occasions, had intervened in circumstances where administrative decisions arguably were not irrational. To this end, the purpose of this article is to assess the constitutionality of these seemingly low standards of irrationality. The author does so by reference either to the manner of review employed—the use of the proportionality principle, for example—or the context of the administrative decision under scrutiny, such as the infringement of the applicant’s fundamental rights. The author finds that the cases from the previous article where low standards of irrationality were arguably adopted were, in fact, legitimate according to these chosen methods of evaluation. However, this is an interim conclusion because, for reasons of word length, the author is unable to complete a full assessment here. It is therefore proposed that a subsequent article will continue to examine the constitutionality of these cases. Furthermore, the author will also try and establish a zone of executive decision-making, for reasons of democracy, where the courts are excluded from irrationality review. If the author is unsuccessful in this regard, the final conclusion of this study will inevitably be that low standards of judicial intervention exist without limit—a clear assault on the constitutional principle stated above

Impact of additional genetic abnormalities at diagnosis of chronic myeloid leukemia for first-line imatinib-treated patients receiving proactive treatment intervention

The BCR::ABL1 gene fusion initiates chronic myeloid leukemia (CML); however, evidence has accumulated from studies of highly selected cohorts that variants in other cancer-related genes are associated with treatment failure. Nevertheless, the true incidence and impact of additional genetic abnormalities (AGA) at diagnosis of chronic phase (CP)-CML is unknown. We sought to determine whether AGA at diagnosis in a consecutive imatinib-treated cohort of 210 patients enrolled in the TIDEL-II trial influenced outcome despite a highly proactive treatment intervention strategy. Survival outcomes including overall survival, progression-free survival, failure-free survival, and BCR::ABL1 kinase domain mutation acquisition were evaluated. Molecular outcomes were measured at a central laboratory and included major molecular response (MMR, BCR::ABL1 ≤0.1%IS), MR4 (BCR::ABL1 ≤0.01%IS), and MR4.5 (BCR::ABL1 ≤0.0032%IS). AGA included variants in known cancer genes and novel rearrangements involving the formation of the Philadelphia chromosome. Clinical outcomes and molecular response were assessed based on the patient's genetic profile and other baseline factors. AGA were identified in 31% of patients. Potentially pathogenic variants in cancer-related genes were detected in 16% of patients at diagnosis (including gene fusions and deletions) and structural rearrangements involving the Philadelphia chromosome (Ph-associated rearrangements) were detected in 18%. Multivariable analysis demonstrated that the combined genetic abnormalities plus the EUTOS long-term survival clinical risk score were independent predictors of lower molecular response rates and higher treatment failure. Despite a highly proactive treatment intervention strategy, first-line imatinib-treated patients with AGA had poorer response rates. These data provide evidence for the incorporation of genomically-based risk assessment for CML

The biogeochemical impact of glacial meltwater from Southwest Greenland

Biogeochemical cycling in high-latitude regions has a disproportionate impact on global nutrient budgets. Here, we introduce a holistic, multi-disciplinary framework for elucidating the influence of glacial meltwaters, shelf currents, and biological production on biogeochemical cycling in high-latitude continental margins, with a focus on the silica cycle. Our findings highlight the impact of significant glacial discharge on nutrient supply to shelf and slope waters, as well as surface and benthic production in these regions, over a range of timescales from days to thousands of years. Whilst biological uptake in fjords and strong diatom activity in coastal waters maintains low dissolved silicon concentrations in surface waters, we find important but spatially heterogeneous additions of particulates into the system, which are transported rapidly away from the shore. We expect the glacially-derived particles – together with biogenic silica tests – to be cycled rapidly through shallow sediments, resulting in a strong benthic flux of dissolved silicon. Entrainment of this benthic silicon into boundary currents may supply an important source of this key nutrient into the Labrador Sea, and is also likely to recirculate back into the deep fjords inshore. This study illustrates how geochemical and oceanographic analyses can be used together to probe further into modern nutrient cycling in this region, as well as the palaeoclimatological approaches to investigating changes in glacial meltwater discharge through time, especially during periods of rapid climatic change in the Late Quaternary

Protein Tyrosine Phosphatase Pez : its role in the regulation of cell-cell adhesions.

The balance of tyrosine phosphorylation in the cell is maintained by the opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Investigation into tyrosine phosphorylation was initially focused on the action of PTKs. However, research over the past decade has revealed that PTPs also play a key role in signal transduction. The multi-protein complexes that constitute the cell-cell adhesions in endothelial and epithelial tissues are dynamically restructured in response to extracellular and intracellular signalling. Tyrosine phosphorylation is involved in the regulation of both adherens junctions and tight junctions. Inhibitors of PTPs have been shown to disrupt cell-cell adhesions indicating that PTPs are important in maintaining adhesion integrity. The maintenance of a selectively permeable barrier is an essential function of endothelial cells, which are the cells that line the lumen of blood vessels. Therefore, it is important to understand the normal functioning of the proteins in the cell-cell adhesion complexes. The aims of this research were to ascertain which members of the PTP family are expressed in human umbilical vein endothelial cells (HUVEC) and to characterise a PTP that may potentially be involved in the regulation of cell-cell adhesions. A homology screen identified a cytosolic phosphatase, PTP-Pez, to be highly expressed in HUVEC. The presence of the protein-protein interaction FERM domain (band 4.1, ezrin, radixin and moesin) at the N-terminus of Pez predicted its localisation to the plasma membrane. Specific antibodies showed that in confluent monolayers Pez is cytoplasmic and concentrated at intercellular junctions but the protein is nuclear in sub-confluent cells. The adherens junction protein β-catenin and the tight junction protein occludin were both identified as potential substrates of Pez using a "substrate-trapping" approach. Data showing that Pez bound to and dephosphorylated β-catenin in vivo further substantiated this. A truncated form of Pez lacking the catalytic domain acted as a dominant negative mutant inhibiting the dephosphorylation of its substrates at intercellular junctions and enhancing cell motility. Canine epithelial cells overexpressing Pez underwent an apparent epithelial to mesenchymal transition (EMT), a process typified by downregulation of cell-cell contacts. These findings indicate that Pez plays a role in the regulation of cell-cell adhesion.Thesis (Ph.D.) -- University of Adelaide, Dept. of Medicine, 200

Estrogen defines the dynamics and destination of transactivated EGF receptor in breast cancer cells: role of S1P3 receptor and Cdc42

This article appeared in Experimental Cell Research, published by Elsevier Ltd. Under Elsevier's copyright, mandated authors are not permitted to make work available in an institutional repository.Sphingosine-1-phosphate (S1P) receptors mediate transactivation of epidermal growth factor receptor (EGFR) by estrogen (E2). Here we report that the amount of intracellular EGFR remains elevated after stimulation of MCF-7 cells with E2 and S1P, although membrane-localized EGFR and S1P3 receptors are quickly internalized. Co-localization of internalized EGFR and LAMP-2 was lower in cells treated with E2/S1P, suggesting that endosomal EGFR might be directed for recycling instead of degradation. In addition, we found that E2/S1P activated Cdc42 and that knockdown of Cdc42 restores fast EGFR degradation after E2/S1P stimulation. Inhibition of S1P3 receptors prevented E2-induced activation of Cdc42, supporting the important role of the S1P receptor in E2 signaling. This is a novel mechanism further defining the effect of E2/S1P on the EGFR transactivation in breast cancer cells.This work was supported by grants from C.M.E. Kelly Cancer Research Foundation and Lyn Wrigley Breast Cancer Research and Development Fund (Flinders Medical Centre, Australia) (to O.S.); and National Health and Medical Research Council of Australia (to P.X.). PX is a Research Fellow of Cancer Institute New South Wales, Australia

A perspective on regulation of cell-cell adhesion and epithelial-mesenchymal transition: Known and novel

A number of recent reviews in the field have described many of the known growth factors and signalling pathways that may be involved in regulating epithelial-mesenchymal transitions. This perspective will focus on some aspects of posttranslational regulation of cell-cell adhesion that are less well understood and their potential role in initiating epithelial-mesenchymal transitions. In addition, a potential novel intermediate in the signalling pathway of epithelial-mesenchymal transition will also be described