Regulation of TRPM8 channel activity by Src-mediated tyrosine phosphorylation

The transient receptor potential melastatin type 8 (TRPM8) receptor channel is expressed in primary afferent neurons where it is the main transducer of innocuous cold temperatures and also in a variety of tumors, where it is involved in progression and metastasis. Modulation of this channel by intracellular signaling pathways has therefore important clinical implications. We investigated the modulation of recombinant and natively expressed TRPM8 by the Src kinase, which is known to be involved in cancer pathophysiology and inflammation. Human TRPM8 expressed in HEK293T cells is constitutively tyrosine phosphorylated by Src which is expressed either heterologously or endogenously. Src action on TRPM8 potentiates its activity, as treatment with PP2, a selective Src kinase inhibitor, reduces both TRPM8 tyrosine phosphorylation and cold‐induced channel activation. RNA interference directed against the Src kinase diminished the extent of PP2‐induced functional downregulation of TRPM8, confirming that PP2 acts mainly through Src inhibition. Finally, the effect of PP2 on TRPM8 cold activation was reproduced in cultured rat dorsal root ganglion neurons, and this action was antagonized by the protein tyrosine phosphatase inhibitor pervanadate, confirming that TRPM8 activity is sensitive to the cellular balance between tyrosine kinases and phosphatases. This positive modulation of TRPM8 by Src kinase may be relevant for inflammatory pain and cancer signaling

Economic Effects of Migration from Poland to the UK

Considering that large numbers of the EU-8 immigrants was a strong argument for the Brexit, the objective of this paper is to assess some economic effects of migration from Poland to the UK for both countries. Intensive emigration of the Poles to the UK since 2004 negatively affected Poland’s economic growth in the long run, but it also reduced tensions at the labour market by decreasing the unemployment rate. On the other hand, the increase in Polish immigrants in the UK did not significantly affect economic growth and unemployment rate in the destination country in the short run in the period 2004-2015. A significance influence was observed only in the long run, when the UK economic growth decreased, but the pressures on the labour market significantly reduced. From these empirical findings, some policy recommendations are required for both countries: for Poland, migration policies to promote the return of migrants and more efficient utilization of labour force, while for the UK – shaping a more flexible labour market

The role of education, individual and economic factors in entrepreneurial initiatives: a microeconomic approach for the Czech republic, Slovakia and Poland

The purpose of this research is to assess the impact of university education and business environment on entrepreneurial initiatives and to make comparisons of the results between students coming from Poland, the Czech Republic and Slovakia. These countries were selected for the analysis since these are three of the V4 countries with common targets regarding the development of business environment and with an important location advantage. The International Visegrad Fund promotes mutual cooperation within the region in various fields, including the development of economic relations (in tourism, education, scientific research, cross-border cooperation). This Fund also implements own projects in these fields. The importance of the research is justified by the identification of the factors that mostly affect entrepreneurial initiatives; these factors could be developed more in order to increase the number of successful businesses in each of these country. Moreover, some obstacles to entrepreneurial initiatives are identified and suitable recommendations are provided to minimize these obstacles

Analysis of EYA3 Phosphorylation by Src Kinase Identifies Residues Involved in Cell Proliferation

Eyes absent (EYA) are non-thiol-based protein tyrosine phosphatases (PTPs) that also have transcriptional co-activator functions. Their PTP activity is involved in various pathologies. Recently, we demonstrated that Src tyrosine kinase phosphorylates human EYA3 by controlling its subcellular localization. We also found EYA3′s ability to autodephosphorylate, while raising the question if the two opposing processes could be involved in maintaining a physiologically adequate level of phosphorylation. Using native and bottom-up mass spectrometry, we performed detailed mapping and characterization of human EYA3 Src-phosphorylation sites. Thirteen tyrosine residues with different phosphorylation and autodephosphorylation kinetics were detected. Among these, Y77, 96, 237, and 508 displayed an increased resistance to autodephosphorylation. Y77 and Y96 were found to have the highest impact on the overall EYA3 phosphorylation. Using cell cycle analysis, we showed that Y77, Y96, and Y237 are involved in HEK293T proliferation. Mutation of the three tyrosine residues abolished the pro-proliferative effect of EYA3 overexpression. We have also identified a Src-induced phosphorylation pattern of EYA3 in these cells. These findings suggest that EYA3′s tyrosine phosphorylation sites are non-equivalent with their phosphorylation levels being under the control of Src-kinase activity and of EYA3′s autodephosphorylation