GTPase Networks in Membrane Traffic Mizuno-Yamasaki, Emi; Rivera-Molina, Felix; Novick, Peter
Annual review of biochemistry,
01/2012, Volume:
81, Issue:
1
Journal Article
Peer reviewed
Open access
Members of the Rab or ARF Sar branches of the Ras GTPase superfamily regulate almost every step of intracellular membrane traffic. A rapidly growing body of evidence indicates that these GTPases do ...not act as lone agents but are networked to one another through a variety of mechanisms to coordinate the individual events of one stage of transport and to link together the different stages of an entire transport pathway. These mechanisms include guanine nucleotide exchange factor (GEF) cascades, GTPase-activating protein (GAP) cascades, effectors that bind to multiple GTPases, and positive-feedback loops generated by exchange factor-effector interactions. Together these mechanisms can lead to an ordered series of transitions from one GTPase to the next. As each GTPase recruits a unique set of effectors, these transitions help to define changes in the functionality of the membrane compartments with which they are associated.
We conduct a systematic and interdisciplinary review of empirical literature assessing evidence on induced innovation in energy and related technologies. We explore links between demand-drivers (both ...market-wide and targeted); indicators of innovation (principally, patents); and outcomes (cost reduction, efficiency, and multi-sector/macro consequences). We build on existing reviews in different fields and assess over 200 papers containing original data analysis. Papers linking drivers to patents, and indicators of cumulative capacity to cost reductions (experience curves), dominate the literature. The former does not directly link patents to outcomes; the latter does not directly test for the causal impact of on cost reductions. Diverse other literatures provide additional evidence concerning the links between deployment, innovation activities, and outcomes. We derive three main conclusions. (a) Demand-pull forces enhance patenting; econometric studies find positive impacts in industry, electricity and transport sectors in all but a few specific cases. This applies to all drivers—general energy prices, carbon prices, and targeted interventions that build markets. (b) Technology costs decline with cumulative investment for almost every technology studied across all time periods, when controlled for other factors. Numerous lines of evidence point to dominant causality from at-scale deployment (prior to self-sustaining diffusion) to cost reduction in this relationship. (c) Overall innovation is cumulative, multi-faceted, and self-reinforcing in its direction (path-dependent). We conclude with brief observations on implications for modelling and policy. In interpreting these results, we suggest distinguishing the economics of active deployment, from more passive diffusion processes, and draw the following implications. There is a role for policy diversity and experimentation, with evaluation of potential gains from innovation in the broadest sense. Consequently, endogenising innovation in large-scale models is important for deriving policy-relevant conclusions. Finally, seeking to relate quantitative economic evaluation to the qualitative socio-technical transitions literatures could be a fruitful area for future research.
This article reviews the history and current issues of wind energy development in Japan and considers the role of policy and future direction of wind energy. Past policy with its weak market focus ...did not increase wind energy share in Japan. The situation surrounding wind and other renewable energy changed dramatically after the Great East Earthquake and Tsunami and the subsequent Fukushima Nuclear Plant Accident in early 2011. The new Feed-in Tariff regime was introduced and the Electricity Sector Reform is slowly progressing. Although wind energy has much larger potential than other renewables in Japan, the FIT has not increased wind installation to date, and the number of bottlenecks has hindered large-scale market deployment of wind. The limited grid capacity, the current electricity market structure, and grid operating practices by the existing Electricity Power Companies have constrained the grid access of wind projects. A layer of regulations related to development permits increases lead-time, project uncertainty, and risk premiums. Difficulty in terms of social acceptance is also high due to some of the past mistakes which did not address local community concerns. Cost of wind energy is also high, compared with other countries, due to lack of economies of scale and other reasons. Japan needs to implement a more comprehensive policy package to address numerous bottlenecks and risks to increase wind energy share in its energy mix.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Ligand-activated receptor tyrosine kinases undergo endocytosis and are transported via endosomes to lysosomes for degradation. This "receptor down-regulation" process is crucial to terminate the cell ...proliferation signals produced by activated receptors. During the process, ubiquitination of the receptors serves as a sorting signal for their trafficking from endosomes to lysosomes. Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells. Immunopurified UBPY deubiquitinated EGFR in vitro. In EGF-stimulated cells, UBPY underwent ubiquitination and bound to EGFR. Overexpression of Hrs or a dominant-negative mutant of SKD1, proteins that play roles in the endosomal sorting of ubiquitinated receptors, caused the accumulation of endogenous UBPY on exaggerated endosomes. A catalytically inactive UBPY mutant clearly localized on endosomes, where it overlapped with EGFR when cells were stimulated with EGF. Finally, depletion of endogenous UBPY by RNA interference resulted in elevated ubiquitination and accelerated degradation of EGF-activated EGFR. We conclude that UBPY negatively regulates the rate of EGFR down-regulation by deubiquitinating EGFR on endosomes.
Sec2p is the guanine nucleotide exchange factor (GEF) that activates the Rab GTPase Sec4p on secretory vesicles. Sec2p also binds a Rab acting earlier in the secretory pathway, Ypt32-GTP, forming a ...Rab GEF cascade. Ypt32p and the Sec4p effector Sec15p (a component of the exocyst complex) compete for binding to Sec2p. Indeed Ypt32p initially recruits Sec2p, but subsequently allows a handoff of active Sec2p/Sec4p to Sec15p. Intriguingly, Golgi-associated phosphatidylinositol 4-phosphate (PI4P) works together with Ypt32-GTP in this context. PI4P inhibits Sec2p-Sec15p interactions, promoting recruitment of Sec2p by Ypt32p as secretory vesicles form. However, PI4P levels appear to decline as vesicles reach secretory sites, allowing Sec15p to replace Ypt32p as vesicles mature. In this way, the regulation of PI4P levels may switch Sec2p/Sec4p function during vesicle maturation, from a Rab GEF recruitment cascade involving Ypt32p to an effector positive feedback loop involving Sec15p.
Display omitted
► Rab GEF Sec2 binds Golgi-derived phosphatidylinositol 4-phosphate (PI4P) ► PI4P inhibits Sec2 binding to the exocyst, freeing Sec2 to bind Ypt32 ► PI4P thus acts in parallel with Ypt32 in Sec2 recruitment ► As PI4P declines, Sec2 engages in a positive feedback loop with the exocyst
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Motor impairments not only lead to a significant reduction in patient activity levels but also trigger a further deterioration in motor function due to deconditioning, which is an issue that is ...particularly pronounced during hospitalization. This deconditioning can be countered by sustaining appropriate activity levels. Activities that occur outside of scheduled programs, often overlooked, are critical in this context. Wearable technology, such as smart clothing, provides a means to monitor these activities.
This study aimed to observe activity levels in patients who had strokes during the subacute phase, focusing on both scheduled training sessions and other nontraining times in an inpatient rehabilitation environment. A smart clothing system is used to simultaneously measure heart rate and acceleration, offering insights into both the amount and intensity of the physical activity.
In this preliminary cohort study, 11 individuals undergoing subacute stroke rehabilitation were enrolled. The 48-hour continuous measurement system, deployed at admission and reassessed 4 weeks later, monitored accelerometry data for physical activity (quantified with a moving SD of acceleration MSDA) and heart rate for intensity (quantified with percent heart rate reserve). The measurements were performed using a wearable activity monitoring system, the hitoe (NTT Corporation and Toray Industries, Inc) system comprising a measuring garment (wear or strap) with integrated electrodes, a data transmitter, and a smartphone. The Functional Independence Measure was used to assess the patients' daily activity levels. This study explored factors such as differences in activity during training and nontraining periods, correlations with activities of daily living (ADLs) and age, and changes observed after 4 weeks.
A significant increase was found in the daily total MSDA after the 4-week program, with the average percent heart rate reserve remaining consistent. Physical activity during training positively correlated with ADL levels both at admission (ρ=0.86, P<.001) and 4 weeks post admission (ρ=0.96, P<.001), whereas the correlation between age and MSDA was not significant during training periods at admission (ρ=-0.41, P=.21) or 4 weeks post admission (ρ=-0.25, P=.45). Conversely, nontraining activity showed a negative correlation with age, with significant negative correlations with age at admission (ρ=-0.82, P=.002) and 4 weeks post admission (ρ=-0.73, P=.01).
Inpatient rehabilitation activity levels were positively correlated with ADL levels. Further analysis revealed a strong positive correlation between scheduled training activities and ADL levels, whereas nontraining activities showed no such correlation. Instead, a negative correlation between nontraining activities and age was observed. These observations suggest the importance of providing activity opportunities for older patients, while it may also suggest the need for adjusting the activity amount to accommodate the potentially limited fitness levels of this demographic. Future studies with larger patient groups are warranted to validate and further elucidate these findings.
Abstract
We conduct a systematic and interdisciplinary review of empirical literature assessing evidence on induced innovation in energy and related technologies. We explore links between ...demand-drivers (both market-wide and targeted); indicators of innovation (principally, patents); and outcomes (cost reduction, efficiency, and multi-sector/macro consequences). We build on existing reviews in different fields and assess over 200 papers containing original data analysis. Papers linking drivers to patents, and indicators of cumulative capacity to cost reductions (experience curves), dominate the literature. The former does not directly link patents to outcomes; the latter does not directly test for the causal impact of on cost reductions. Diverse other literatures provide additional evidence concerning the links between deployment, innovation activities, and outcomes. We derive three main conclusions. (a) Demand-pull forces enhance patenting; econometric studies find positive impacts in industry, electricity and transport sectors in all but a few specific cases. This applies to all drivers—general energy prices, carbon prices, and targeted interventions that build markets. (b) Technology costs decline with cumulative investment for almost every technology studied across all time periods, when controlled for other factors. Numerous lines of evidence point to dominant causality from at-scale deployment (prior to self-sustaining diffusion) to cost reduction in this relationship. (c) Overall innovation is cumulative, multi-faceted, and self-reinforcing in its direction (path-dependent). We conclude with brief observations on implications for modelling and policy. In interpreting these results, we suggest distinguishing the economics of active deployment, from more passive diffusion processes, and draw the following implications. There is a role for policy diversity and experimentation, with evaluation of potential gains from innovation in the broadest sense. Consequently, endogenising innovation in large-scale models is important for deriving policy-relevant conclusions. Finally, seeking to relate quantitative economic evaluation to the qualitative socio-technical transitions literatures could be a fruitful area for future research.
Monoubiquitination of endocytosed cell surface receptors serves as a sorting signal for their trafficking from endosomes to lysosomes. The sorting of ubiquitinated proteins is executed by concerted ...actions of class E vacuolar protein sorting (Vps) proteins. Some proteins in the sorting machinery undergo monoubiquitination, suggesting that their functions are also regulated by ubiquitination. The Hrs–STAM complex, a class E Vps protein complex essential for the initial step of the sorting pathway, binds two deubiquitinating enzymes, UBPY and AMSH. Here we examined the effects of inactivating UBPY on protein ubiquitination at endosomes. Overexpression of a catalytically inactive UBPY mutant or depletion of UBPY by RNA interference resulted in the accumulation of ubiquitinated proteins on morphologically aberrant endosomes. Electron microscopy showed that they are aggregates of multivesicular endosomes. Among the sorting machinery proteins that undergo ubiquitination, Eps15 was monoubiquitinated at an elevated level in UBPY‐inactivated cells. UBPY also deubiquitinated Eps15 in vitro, suggesting that Eps15 is a cellular substrate for UBPY. Furthermore, inactivation of UBPY caused the accumulation of Eps15 on the endosomal aggregates. These results suggest that UBPY regulates the level of protein ubiquitination on endosomes, which is required for maintaining the morphology of the organelle.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Sec2p is a guanine nucleotide exchange factor that promotes exocytosis by activating the Rab GTPase Sec4p. Sec2p is highly phosphorylated, and we have explored the role of phosphorylation in the ...regulation of its function. We have identified three phosphosites and demonstrate that phosphorylation regulates the interaction of Sec2p with its binding partners Ypt32p, Sec15p, and phosphatidyl-inositol-4-phosphate. In its nonphosphorylated form, Sec2p binds preferentially to the upstream Rab, Ypt32p-GTP, thus forming a Rab guanine nucleotide exchange factor cascade that leads to the activation of the downstream Rab, Sec4p. The nonphosphorylated form of Sec2p also binds to the Golgi-associated phosphatidyl-inositol-4-phosphate, which works in concert with Ypt32p-GTP to recruit Sec2p to Golgi-derived secretory vesicles. In contrast, the phosphorylated form of Sec2p binds preferentially to Sec15p, a downstream effector of Sec4p and a component of the exocyst tethering complex, thus forming a positive-feedback loop that prepares the secretory vesicle for fusion with the plasma membrane. Our results suggest that the phosphorylation state of Sec2p can direct a switch in its regulatory binding partners that facilitates maturation of the secretory vesicle and helps to promote the directionality of vesicular transport.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
During cytokinesis, the central spindle, a bundle of interdigitated anti-parallel microtubules between separating chromosomes, recruits various cytokinetic regulator proteins to the cleavage region. ...Here, we show that the level of protein ubiquitylation is strikingly and transiently elevated in Aurora B kinase-positive double-band regions of the central spindle during cytokinesis. Two deubiquitylating enzymes UBPY and AMSH, which act on endosomes in interphase, were also recruited to the cleavage region. Whereas UBPY was detected only in the final stage of cytokinesis at the midbody, AMSH localized to a ring structure surrounding the mitotic kinesin MKLP1-positive region of the central spindle and midbody throughout cytokinesis. Depletion of cellular UBPY or AMSH led to defects in cytokinesis. VAMP8, a v-SNARE required for vesicle fusion in cytokinesis, localized to the central spindle region positive for ubiquitylated proteins, and underwent ubiquitylation and deubiquitylation by both UBPY and AMSH. Our results thus implicate the ubiquitylation/deubiquitylation of proteins including VAMP8 in cytokinesis.
PDF
