A recent genome-wide association study identified the gene encoding lemur tyrosine kinase-2 (LMTK2) as a susceptibility gene for prostate cancer. The identified genetic alteration is within intron 9, ...but the mechanisms by which LMTK2 may impact upon prostate cancer are not clear because the functions of LMTK2 are poorly understood. Here, we show that LMTK2 regulates a known pathway that controls phosphorylation of kinesin-1 light chain-2 (KLC2) by glycogen synthase kinase-3β (GSK3β). KLC2 phosphorylation by GSK3β induces the release of cargo from KLC2. LMTK2 signals via protein phosphatase-1C (PP1C) to increase inhibitory phosphorylation of GSK3β on serine-9 that reduces KLC2 phosphorylation and promotes binding of the known KLC2 cargo Smad2. Smad2 signals to the nucleus in response to transforming growth factor-β (TGFβ) receptor stimulation and transport of Smad2 by kinesin-1 is required for this signalling. We show that small interfering RNA loss of LMTK2 not only reduces binding of Smad2 to KLC2, but also inhibits TGFβ-induced Smad2 signalling. Thus, LMTK2 may regulate the activity of kinesin-1 motor function and Smad2 signalling.
We report the occurrence of a deep low state in the eclipsing short-period cataclysmic variable (CV) IR Com, lasting more than two years. Spectroscopy obtained in this state shows the system as a ...detached white dwarf plus low-mass companion, indicating that accretion has practically ceased. The spectral type of the companion derived from the SDSS spectrum is M6–7, somewhat later than expected for the orbital period of IR Com. Its radial velocity amplitude, K
2 = 419.6 ± 3.4 km s−1, together with the inclination of 75°–90° implies 0.8 < Mwd <1.0 M⊙. We estimate the white dwarf temperature to be ≃15 000 K, and the absence of Zeeman splitting in the Balmer lines rules out magnetic fields in excess of ≃5 MG. IR Com still defies an unambiguous classification, in particular the occurrence of a deep, long low state is so far unique among short-period CVs that are not strongly magnetic.
We present early results from the JCMT (James Clerk Maxwell Telescope) Plane Survey (JPS), which has surveyed the northern inner Galactic plane between longitudes ... = 7... and ... = 63... in the ...850-...m continuum with SCUBA-2 (Submm Common-User Bolometer Array 2), as part of the JCMT Legacy Survey programme. Data from the ... = 30... survey region, which contains the massive-star-forming regions W43 and G29.96, are analysed after approximately 40 per cent of the observations had been completed. The pixel-to-pixel noise is found to be 19 mJy beam... after a smooth over the beam area, and the projected equivalent noise levels in the final survey are expected to be around 10 mJy beam... An initial extraction of compact sources was performed using the FellWalker method, resulting in the detection of 1029 sources above a 5... surface-brightness threshold. The completeness limits in these data are estimated to be around 0.2 Jy beam... (peak flux density) and 0.8 Jy (integrated flux density) and are therefore probably already dominated by source confusion in this relatively crowded section of the survey. The flux densities of extracted compact sources are consistent with those of matching detections in the shallower APEX (Atacama Pathfinder Experiment) Telescope Large Area Survey of the Galaxy (ATLASGAL) survey. We analyse the virial and evolutionary state of the detected clumps in the W43 star-forming complex and find that they appear younger than the Galactic-plane average. (ProQuest: ... denotes formulae/symbols omitted.)
Kinesin light chain 1 (KLC1) binds to the intracellular cytoplasmic domain of the type-1 membrane-spanning protein calsyntenin-1 (also known as alcadein-α) to mediate transport of a subset of ...vesicles. Here, we identify serine 460 in KLC1 (KLC1ser460) as a phosphorylation site and show that mutation of KLC1ser460 influences the binding of KLC1 to calsyntenin-1. Mutation of KLC1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residue, to mimic permanent phosphorylation, reduced the binding. Mutation of KLC1ser460 did not affect the interaction of KLC1 with four other known binding partners: huntingtin-associated protein 1 isoform A (HAP1A), collapsin response mediator protein-2 (CRMP2), c-Jun N-terminal kinase-interacting protein-1 (JIP1) and kinase-D-interacting substrate of 220 kDa (Kidins220). KLC1ser460 is a predicted mitogen-activated protein kinase (MAPK) target site, and we show that extracellular-signal-regulated kinase (ERK) phosphorylates this residue in vitro. We also demonstrate that inhibition of ERK promotes binding of calsyntenin-1 to KLC1. Finally, we show that expression of the KLC1ser460 mutant proteins influences calsyntenin-1 distribution and transport in cultured cells. Thus, phosphorylation of KLC1ser460 represents a mechanism for selectively regulating the binding and trafficking of calsyntenin-1.
J. Neurochem. (2012) 121, 343–348.
Cyclin‐dependent kinase‐5 (cdk5)/p35 and protein phosphatase‐1 (PP1) are two major enzymes that control a variety of physiological processes within the nervous ...system including neuronal differentiation, synaptic plasticity and axonal transport. Defective cdk5/p35 and PP1 function are also implicated in several major human neurodegenerative diseases. Cdk5/p35 and the catalytic subunit of PP1 (PP1C) both bind to the brain‐enriched, serine–threonine kinase lemur tyrosine kinase‐2 (LMTK2). Moreover, LMTK2 phosphorylates PP1C on threonine‐320 (PP1Cthr320) to inhibit its activity. Here, we demonstrate that LMTK2 is phosphorylated on serine‐1418 (LMTK2ser1418) by cdk5/p35 and present evidence that this regulates its ability to phosphorylate PP1Cthr320. We thus describe a new signalling pathway within the nervous system that links cdk5/p35 with PP1C and which has implications for a number of neuronal functions and neuronal dysfunction.
Lemur tyrosine kinase‐2 links cdk5/p35 to protein phosphatase‐1 and downstream targets such as GSK3β. Cdk5/p35 is a kinase that regulates a variety of neuronal functions. One route whereby it fulfils these functions is by inducing the inhibitory phosphorylation of protein phosphatase‐1C, which then signals to downstream targets such as GSK3β. In this issue, Manser et al. demonstrate that cdk5/p35‐mediated phosphorylation of PP1C involves lemur tyrosine kinase‐2. Cdk5/p35 phosphorylates LMTK2 to stimulate LMTK2 phosphorylation of PP1C.
ABSTRACT
We present and validate the catalogue of Lyman-α forest fluctuations for 3D analyses using the Early Data Release (EDR) from the Dark Energy Spectroscopic Instrument (DESI) survey. We used ...88 511 quasars collected from DESI Survey Validation (SV) data and the first two months of the main survey (M2). We present several improvements to the method used to extract the Lyman-α absorption fluctuations performed in previous analyses from the Sloan Digital Sky Survey (SDSS). In particular, we modify the weighting scheme and show that it can improve the precision of the correlation function measurement by more than 20 per cent. This catalogue can be downloaded from https://data.desi.lbl.gov/public/edr/vac/edr/lya/fuji/v0.3, and it will be used in the near future for the first DESI measurements of the 3D correlations in the Lyman-α forest.
We present the second paper of a series of publications aiming at obtaining a better understanding regarding the nature of type Ia supernovae (SN Ia) progenitors by studying a large sample of ...detached F, G and K main-sequence stars in close orbits with white dwarf companions (i.e. WD+FGK binaries). We employ the Large Sky Area Multi-Object Fibre Spectroscopic Telescope (LAMOST) data release 4 spectroscopic data base together with Galaxy Evolution Explorer (GALEX) ultraviolet fluxes to identify 1549 WD+FGK binary candidates (1057 of which are new), thus doubling the number of known sources.We measure the radial velocities of 1453 of these binaries from the available LAMOST spectra and/or from spectra obtained by us at a wide variety of different telescopes around the globe. The analysis of the radial velocity data allows us to identify 24 systems displaying more than 3s radial velocity variation that we classify as close binaries. We also discuss the fraction of close binaries among WD+FGK systems, which we find to be ~10 per cent, and demonstrate that high-resolution spectroscopy is required to efficiently identify double-degenerate SNIa progenitor candidates.
Peer Reviewed
We demonstrate here that Chinese hamster ovary cells stably expressing PRL-3, a M(r) 20000 prenylated protein tyrosine phosphatase, or its relative, PRL-1, exhibit enhanced motility and invasive ...activity. A catalytically inactive PRL-3 mutant has significantly reduced migration-promoting activity. We observe that PRL-3 is associated with diverse membrane structures involved in cell movement. Furthermore, we show that PRL-3- and -1-expressing cells, but not control cells, induce metastatic tumor formation in mice. Thus, our results deliver the first evidence for a causative role of PRL-3 and -1 in promoting cell motility, invasion activity, and metastasis.
Riluzole is the only drug approved for the treatment of amyotrophic lateral sclerosis (ALS) but its precise mode of action is not properly understood. Damage to axonal transport of neurofilaments is ...believed to be part of the pathogenic mechanism in ALS and this has been linked to defective glutamate handling and increased phosphorylation of neurofilament side-arm domains. Here, we show that riluzole protects against glutamate-induced slowing of neurofilament transport. Protection is associated with decreased neurofilament side-arm phosphorylation and inhibition of the activities of two neurofilament kinases, ERK and p38 that are activated in ALS. Thus, the anti-glutamatergic properties of riluzole include protection against glutamate-induced changes to neurofilament phosphorylation and transport.
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