Competitive Regulation of E-Cadherin JuxtaMembrane Domain Degradation by p120-Catenin Binding and Hakai-Mediated Ubiquitination

p120-Catenin binding to, and Hakai-mediated ubiquitination of the E-cadherin juxtamembrane domain (JMD) are thought to be involved in regulating E-cadherin internalization and degradation. However, the relationship between these two pathways is not understood. We targeted the E-cadherin JMD to mitochondria (WT-JMD) to isolate this domain from the plasma membrane and internalization, and to examine protein modifications and degradation. WT-JMD localized to mitochondria, but did not accumulate there except when proteasome activity was inhibited. We found WT-JMD was ubiquitinated, and arginine substitution of lysines at position 5 (K5R) and 83 (K83R) resulted in the stable accumulation of mutant JMD at mitochondria. p120-Catenin did not localize, or bind to WT-JMD even upon proteasome inhibition, whereas the K5,83R-JMD mutant bound and localized p120-catenin to mitochondria. Mutation of the p120-catenin binding site in combination with these lysine mutations inhibited p120-catenin binding, but did not decrease JMD stability or its accumulation at mitochondria. Thus, increased stability of JMD lysine mutants was due to inhibition of ubiquitination and not to p120-catenin binding. Finally, mutation of these critical lysines in full length E-cadherin had similar effects on protein stability as WT-JMD. Our results indicate that ubiquitination of the JMD inhibits p120-catenin binding, and targets E-cadherin for degradation

Sequence and Structure Signatures of Cancer Mutation Hotspots in Protein Kinases

Protein kinases are the most common protein domains implicated in cancer, where somatically acquired mutations are known to be functionally linked to a variety of cancers. Resequencing studies of protein kinase coding regions have emphasized the importance of sequence and structure determinants of cancer-causing kinase mutations in understanding of the mutation-dependent activation process. We have developed an integrated bioinformatics resource, which consolidated and mapped all currently available information on genetic modifications in protein kinase genes with sequence, structure and functional data. The integration of diverse data types provided a convenient framework for kinome-wide study of sequence-based and structure-based signatures of cancer mutations. The database-driven analysis has revealed a differential enrichment of SNPs categories in functional regions of the kinase domain, demonstrating that a significant number of cancer mutations could fall at structurally equivalent positions (mutational hotspots) within the catalytic core. We have also found that structurally conserved mutational hotspots can be shared by multiple kinase genes and are often enriched by cancer driver mutations with high oncogenic activity. Structural modeling and energetic analysis of the mutational hotspots have suggested a common molecular mechanism of kinase activation by cancer mutations, and have allowed to reconcile the experimental data. According to a proposed mechanism, structural effect of kinase mutations with a high oncogenic potential may manifest in a significant destabilization of the autoinhibited kinase form, which is likely to drive tumorigenesis at some level. Structure-based functional annotation and prediction of cancer mutation effects in protein kinases can facilitate an understanding of the mutation-dependent activation process and inform experimental studies exploring molecular pathology of tumorigenesis

What makes a terrestrial ecosystem resilient?

A complex set of biotic and abiotic factors determines the resilience of an ecosystem</jats:p

Nitrogen cycle impacts on CO2 fertilisation and climate forcing of land carbon stores

Anthropogenic fossil fuel burning increases atmospheric carbon dioxide (CO2) concentration, which is adjusting the climate system. The direct impact of rising CO2 levels and climate feedback alters the terrestrial carbon stores. Land stores are presently increasing, offsetting a substantial fraction of CO2 emissions. Less understood is how this human-induced carbon cycle perturbation interacts with other terrestrial biogeochemical cycles. These connections require quantification, as they may eventually suppress land fertilisation, and so fewer emissions are allowed to follow any prescribed future global warming pathway. Using the new JULES-CN large-scale land model, which contributed to CMIP6 as the land component of the UKESM1 climate model, we focus on how the introduction of the simulated terrestrial nitrogen (N) cycle modulates the expected evolution of vegetation and soil carbon pools. We find that the N-cycle suppresses, by approximately one-third, any future gains by the global soil pool when compared to calculations without that cycle. There is also a decrease in the vegetation carbon gain, although this is much smaller. Factorial simulations illustrate that N suppression tracks direct CO2 rise rather than climate change. The finding that this CO2-related effect predominantly influences soil carbon rather than vegetation carbon, we explain by different balances between changing carbon uptake levels and residence times. Finally, we discuss how this new generation of land models may gain further from emerging point knowledge held by the detailed ecological modelling community

Common mechanisms explain nitrogen-dependent growth of Arctic shrubs over three decades despite heterogeneous trends and declines in soil nitrogen availability

— Heterogeneity has been observed in the responses of Arctic shrubs to climate variability over recent decades, which may reflect landscape-scale variability in belowground resources. At a northern fringe of tall shrub expansion (Yuribei, Yamal Peninsula, Russia), we sought to determine the mechanisms relating nitrogen (N) limitation to shrub growth over decadal time. — We analysed the ratio of 15N to 14N isotopes in wood rings of 10 Salix lanata individuals (399 measurements) to reconstruct annual point-based bioavailable N between 1980 and 2013. We applied a model-fitting/model-selection approach with a suite of competing ecological models to assess the most-likely mechanisms that explain each shrub’s individual time-series. — Shrub δ15N time-series indicated declining (seven shrubs), increasing (two shrubs) and no trend (one shrub) in N availability. The most appropriate model for all shrubs included N-dependent growth of linear rather than saturating form. Inclusion of plant–soil feedbacks better explained ring width and δ15N for eight of 10 individuals. — Although N trajectories were individualistic, common mechanisms of varying strength confirmed the N-dependency of shrub growth. The linear mechanism may reflect intense scavenging of scarce N; the importance of plant–soil feedbacks suggests that shrubs subvert the microbial bottleneck by actively controlling their environment.</p

International Journal of Water Gouvernance

A tool to measure the potential ecological impact (footprint) of developments outside of protected areas is novel and long overdue. Whilst there are numerous methods currently available for mapping important regions for conservation within protected areas, there are few suitable tools available for assessing the ecological value of landscapes that are 'beyond the reserves'. Given that this accounts for over 88% of the world's terrestrial surface, a systematic tool for determining the ecological value of these landscapes could be relevant to any industrial development that results in a parcel of land being transformed from 'natural' to 'industrial'. Results are presented of a joint project between Statoil and University of Oxford, UK to develop an automatic web-based tool that can assess the ecological value of land outside of protected areas. Ecological factors currently considered within this tool include i) biodiversity, ii) vulnerability, iii) fragmentation, iv) connectivity and v) resilience. The tool has the capability to provide ecological valuations for parcels of land at 300m resolution and uses data that are publicly available and have mostly global coverage. We present results for three case study areas in Canada, Algeria and the Russian Federation to demonstrate its potential and how it can be used to plan development within a concession area in order that damage to local ecosystems and ecosystem functioning is minimized. Copyright 2011, Society of Petroleum Engineers

Ecotoxicity of microplastics to freshwater biota: considering exposure and hazard across trophic levels

In contrast to marine ecosystems, the toxicity impact of microplastics in freshwater environments is poorly understood. This contribution reviews the literature on the range of effects of microplastics across and between trophic levels within the freshwater environment, including biofilms, macrophytes, phytoplankton, invertebrates, fish and amphibians. While there is supporting evidence for toxicity in some species e.g. growth reduction for photoautotrophs, increased mortality for some invertebrates, genetic changes in amphibians, and cell internalization of microplastics and nanoplastics in fish; other studies show that it is uncertain whether microplastics can have detrimental long-term impacts on ecosystems. Some taxa have yet to be studied e.g. benthic diatoms, while only 12% of publications on microplastics in freshwater, demonstrate trophic transfer in foodwebs. The fact that just 2% of publications focus on microplastics colonized by biofilms is hugely concerning given the cascading detrimental effects this could have on freshwater ecosystem function. Multiple additional stressors including environmental change (temperature rises and invasive species) and contaminants of anthropogenic origin (antibiotics, metals, pesticides and endocrine disruptors) will likely exacerbate negative interactions between microplastics and freshwater organisms, with potentially significant damaging consequences to freshwater ecosystems and foodwebs

Remote assessment of locally important ecological features across landscapes: how representative of reality?

The local ecological footprinting tool (LEFT) uses globally available databases, modeling, and algorithms to, remotely assess locally important ecological features across landscapes based on five criteria: biodiversity (beta-diversity), vulnerability (threatened species), fragmentation, connectivity, and resilience. This approach can be applied to terrestrial landscapes at a 300-m resolution within a given target area. Input is minimal (latitude and longitude) and output is a computer-generated report and series of maps that both individually and synthetically depict the relative value of each ecological criteria. A key question for any such tool, however, is how representative is the remotely obtained output compared to what is on the ground. Here, we present the results from comparing remotely- vs. field-generated outputs from the LEFT tool on two distinct study areas for beta-diversity and distribution of threatened species (vulnerability), the two fields computed by LEFT for which such an approach is feasible. The comparison method consists of a multivariate measure of similarity between two fields based on discrete wavelet transforms, and reveals consistent agreement across a wide range of spatial scales. These results suggest that remote assessment tools such as LEFT hold great potential for determining key ecological features across landscapes and for being utilized in preplanning biodiversity assessment tools