Innate or acquired resistance to small molecule BRAF or MEK1/2 inhibitors (BRAFi or MEKi) typically arises through mechanisms that sustain or reinstate ERK1/2 activation. This has led to the ...development of a range of ERK1/2 inhibitors (ERKi) that either inhibit kinase catalytic activity (catERKi) or additionally prevent the activating pT-E-pY dual phosphorylation of ERK1/2 by MEK1/2 (dual-mechanism or dmERKi). Here, we show that eight different ERKi (both catERKi or dmERKi) drive the turnover of ERK2, the most abundant ERK isoform, with little or no effect on ERK1. Thermal stability assays show that ERKi do not destabilise ERK2 (or ERK1) in vitro, suggesting that ERK2 turnover is a cellular consequence of ERKi binding. ERK2 turnover is not observed upon treatment with MEKi alone, suggesting it is ERKi binding to ERK2 that drives ERK2 turnover. However, MEKi pre-treatment, which blocks ERK2 pT-E-pY phosphorylation and dissociation from MEK1/2, prevents ERK2 turnover. ERKi treatment of cells drives the poly-ubiquitylation and proteasome-dependent turnover of ERK2 and pharmacological or genetic inhibition of Cullin-RING E3 ligases prevents this. Our results suggest that ERKi, including current clinical candidates, act as 'kinase degraders', driving the proteasome-dependent turnover of their major target, ERK2. This may be relevant to the suggestion of kinase-independent effects of ERK1/2 and the therapeutic use of ERKi.
A comparison is made of the light curves and and dust production of the initial target for the ROSETTA mission, 46P/Wirtanen and the new target 67P/Churyumov-Gerasimenko during their recent 2002/2003 ...apparition. The study is based on amateur CCD monitoring using a standardised method to produce consistent photometry in Johnson-Kron-Cousins system. Although the dust production of the two comets is similar at perihelion (Af rho approximately 200-cm), dust production in 46P/Wirtanen peaked before perihelion, while in 67P/Churyumov-Gerasimenko it peaks after perihelion. Dust activity shows the same post-perihelion dependence with heliocentric distance in both comets. Overall 67P/Churyumov-Gerasimenko has a dust production rate an order of magnitude greater at the same heliocentric distance post-perihelion as 46P/Wirtanen, but 46P/Wirtanen has greater maximum dust production immediately prior to perihelion.
The near-Earth asteroid 308635 (2005 YU55) is a potentially hazardous asteroid which was discovered in 2005 and passed Earth on Nov. 8, 2011 at 0.85 lunar distances. This was the closest known ...approach by an asteroid of several hundred metres in diameter since 1976 when an object of similar size passed at 0.5 lunar distances. We observed 2005 YU55 from the ground with a recently developed mid-IR camera (miniTAO/MAX38) in N and Q bands and with the Submillimeter Array (SMA) at 1.3 mm. In addition, we obtained space observations with Herschel/PACS at 70, 100, and 160 μm. Our thermal measurements cover a wide range of wavelengths from 8.9 μm to 1.3 mm and were taken after opposition at phase angles between –97° and –18°. We performed a radiometric analysis via a thermophysical model and combined our derived properties with results from radar, adaptive optics, lightcurve observations, speckle, and auxiliary thermal data. We find that 308635 (2005 YU55) has an almost spherical shape with an effective diameter of 300 to 312 m and a geometric albedo pV of 0.055 to 0.075. Its spin axis is oriented towards celestial directions (λecl, βecl) = (60° ± 30°, –60° ± 15°), which means it has a retrograde sense of rotation. The analysis of all available data combined revealed a discrepancy with the radar-derived size. Our radiometric analysis of the thermal data together with the problem to find a unique rotation period might be connected to a non-principal axis rotation. A low to intermediate level of surface roughness (rms mean slope in the range 0.1–0.3) is required to explain the available thermal measurements. We found a thermal inertia in the range 350−800 Jm-2 s-0.5 K-1, very similar to the rubble-pile asteroid 25 143 Itokawa and indicating a surface with a mixture of low conductivity fine regolith with larger rocks and boulders of high thermal inertia.
The blazar OJ 287 has produced two major optical outburst events during the years 2005-2008. These are the latest in a series of outbursts that have occurred repeatedly at 12 year intervals since ...early 1900s. It has been possible to explain the historical light curve fairly well by using a binary black hole model where the secondary black hole impacts the accretion disk of the primary twice during the 12 year orbital cycle. We will ask here how well does the latest light-curve fit with this model. We use a 10 million particle disk to model the accretion disk of the primary black hole. The rate of transfer of particles through the 10 Schwarzschild radius cylinder around the primary is followed. The secondary induces an inward flow through this surface. The inward flow rate is compared with the historical light curve as well as with the most recent observations reported in this paper. The observations have been carried out by using a number of small and medium size telescopes in different locations in order to ensure a dense light-curve coverage. The 'inflow light curve' and the optical light curve of OJ 287 have a close resemblance to each other. It suggests that the tidally induced accretion flow is responsible for the main features of the optical light curve, with the exception of the quasi-periodic double peaks. It implies a close connection between the accretion disk and the jet where the optical synchrotron emission is presumably generated.
The RAS-regulated RAF-MEK1/2-ERK1/2 signaling pathway is frequently deregulated in cancer due to activating mutations of growth factor receptors, RAS or BRAF. Both RAF and MEK1/2 inhibitors are ...clinically approved and various ERK1/2 inhibitors (ERKi) are currently undergoing clinical trials. To date, ERKi display two distinct mechanisms of action (MoA): catalytic ERKi solely inhibit ERK1/2 catalytic activity, whereas dual mechanism ERKi additionally prevents the activating phosphorylation of ERK1/2 at its T-E-Y motif by MEK1/2. These differences may impart significant differences in biological activity because T-E-Y phosphorylation is the signal for nuclear entry of ERK1/2, allowing them to access many key transcription factor targets. Here, we characterized the MoA of five ERKi and examined their functional consequences in terms of ERK1/2 signaling, gene expression, and antiproliferative efficacy. We demonstrate that catalytic ERKi promote a striking nuclear accumulation of p-ERK1/2 in KRAS-mutant cell lines. In contrast, dual-mechanism ERKi exploits a distinct binding mode to block ERK1/2 phosphorylation by MEK1/2, exhibit superior potency, and prevent the nuclear accumulation of ERK1/2. Consequently, dual-mechanism ERKi exhibit more durable pathway inhibition and enhanced suppression of ERK1/2-dependent gene expression compared with catalytic ERKi, resulting in increased efficacy across BRAF- and RAS-mutant cell lines.
Thermal emission from Kuiper belt object (136108) Haumea was measured with Herschel-PACS at 100 mum and 160 mum for almost a full rotation period. Observations clearly indicate a 100 mum thermal ...lightcurve with an amplitude of a factor of ~2, which is positively correlated with the optical lightcurve. This confirms that both are primarily due to shape effects. A 160 mum lightcurve is marginally detected. Radiometric fits of the mean Herschel- and Spitzer- fluxes indicate an equivalent diameter D ~ 1300 km and a geometric albedo pv ~ 0.70-0.75. These values agree with inferences from the optical lightcurve, supporting the hydrostatic equilibrium hypothesis. The large amplitude of the 100 mum lightcurve suggests that the object has a high projected a/b axis ratio (~1.3) and a low thermal inertia as well as possible variable infrared beaming. This may point to fine regolith on the surface, with a lunar-type photometric behavior. The quality of the thermal data is not sufficient to clearly detect the effects of a surface dark spot.
The protein kinases ERK1/2 and RSK associate in unstimulated cells but must separate to target other substrates. In this issue, Gógl et al. show that phosphorylation of RSK by active ERK1/2 ...culminates in the formation of an intramolecular charge clamp between Lys729 and the phosphate group on Ser732. This promotes the dissociation of ERK1/2 from RSK allowing them to engage with other targets.
Light curves and images of 67P/Churyumov-Gerasimenko are presented for the 2002–2003 apparition based on amateur CCD monitoring using a standardised method to produce consistent photometry in ...Johnson-Kron-Cousins system. Multiaperture data shows a large outburst at perihelion during which dust production increased by a factor of 2 to give a peak value of $Af\rho \approx350$ cm. A similar outburst was seen at the same epoch of the previous apparition in 1995–96 and probably in 1982–83, suggesting that the light curve is similar at succesive returns. A considerable change is seen in the slope of the light curve at $r=1.85$ AU ($T+140$ days) corresponding to a second significant increase in dust production. Overall though the dust production shows a very steep dependence with heliocentric distance, falling as r-5.8.
Comet C/2006 W3 (Christensen) was observed in November 2009 at 3.3 AU from the Sun with Herschel.The PACS instrument acquired images of the dust coma in 70-μm and 160-μm filters and spectra covering ...several H2O rotational lines. Spectra in the range 450–1550 GHz were acquired with SPIRE. The comet emission continuum from 70 to 672 μm was measured, but no lines were detected. The spectral energy distribution indicates thermal emission from large particles and provides a measure of the size distribution index and dust production rate. The upper limit to the water production rate is compared to the production rates of other species (CO, CH3OH, HCN, H2S, OH) measured with the IRAM 30-m and Nançay telescopes. The coma is found to be strongly enriched in species more volatile than water, in comparison to comets observed closer to the Sun. The CO to H2O production rate ratio exceeds 220%. The dust-to-gas production rate ratio is on the order of 1.
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