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5. Assembly of nuclear dimers of PI3K regulatory subunits is regulated by the Cdc42-activated tyrosine kinase ACK

Author

Natasha S. Clayton, Millie Fox, Jose J. Vicenté-Garcia, Courtney M. Schroeder, Trevor D. Littlewood, Jonathon I. Wilde, Kadalmani Krishnan, Murray J.B. Brown, Claire Crafter, Helen R. Mott, Darerca Owen, Owen, Darerca [0000-0003-0978-5425], and Apollo - University of Cambridge Repository

Subjects
p85 dimers, Cell Nucleus, p110-independent p85, activated Cdc42 kinase, tyrosine kinase, Cell Biology, Protein-Tyrosine Kinases, Biochemistry, protein phosphorylation, Phosphatidylinositol 3-Kinases, HEK293 Cells, PI3Kinase, nuclear signaling, protein degradation, cancer, Humans, Cdc42, Phosphorylation, Protein Multimerization, Molecular Biology, Signal Transduction
Abstract

Activated Cdc42-associated kinase (ACK) is an oncogenic nonreceptor tyrosine kinase associated with poor prognosis in several human cancers. ACK promotes proliferation, in part by contributing to the activation of Akt, the major effector of class 1A phosphoinositide 3-kinases (PI3Ks), which transduce signals via membrane phosphoinositol lipids. We now show that ACK also interacts with other key components of class 1A PI3K signaling, the PI3K regulatory subunits. We demonstrate ACK binds to all five PI3K regulatory subunit isoforms and directly phosphorylates p85α, p85β, p50α, and p55α on Tyr607 (or analogous residues). We found that phosphorylation of p85β promotes cell proliferation in HEK293T cells. We demonstrate that ACK interacts with p85α exclusively in nuclear-enriched cell fractions, where p85α phosphorylated at Tyr607 (pTyr607) also resides, and identify an interaction between pTyr607 and the N-terminal SH2 domain that supports dimerization of the regulatory subunits. We infer from this that ACK targets p110-independent p85 and further postulate that these regulatory subunit dimers undertake novel nuclear functions underpinning ACK activity. We conclude that these dimers represent a previously undescribed mode of regulation for the class1A PI3K regulatory subunits and potentially reveal additional avenues for therapeutic intervention.

Published
2022
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6. Assembly of nuclear dimers of PI3K regulatory subunits is regulated by the Cdc42-activated tyrosine kinase ACK

Author

Clayton, Natasha S., primary, Fox, Millie, additional, Vicenté-Garcia, Jose J., additional, Schroeder, Courtney M., additional, Littlewood, Trevor D., additional, Wilde, Jonathon I., additional, Krishnan, Kadalmani, additional, Brown, Murray J.B., additional, Crafter, Claire, additional, Mott, Helen R., additional, and Owen, Darerca, additional

Published
2022
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8. Mapping Medusae Fossae Formation materials in the southern highlands of Mars

Author

Harrison, S.K., Balme, M.R., Hagermann, A., Murray, J.B., and Muller, J-P.

Subjects
Mars (Planet) -- Analysis, Astronomy, Earth sciences
Abstract

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.icarus.2010.04.016 Byline: S.K. Harrison (a)(b), M.R. Balme (b), A. Hagermann (a), J.B. Murray (b), J-P. Muller (c) Keywords: Mars; Mars, Surface; Geological processes Abstract: The Medusae Fossae Formation (MFF) is an extensive deposit (2.2x10.sup.6 km.sup.2, Bradley, B.A., Sakimoto, S.E.H., Frey, H., Zimbelman, J.R. [2002]. J. Geophys. Res. 107, 5058) of wind-eroded material of widely debated origin, which unconformably overlies a considerable area of the crustal dichotomy boundary on Mars. The MFF shows a variety of layering patterns, erosional styles and channel-like forms and has been mapped into five main outcrops and three geological members according to exposure and stratigraphy (Scott, D.H., Tanaka, K.L., 1986. USGS Map I-1802-A; Greeley, R., Guest, J.E., 1987. Map I-1802-B; Zimbelman, J.R., Crown, D., Jenson, D., 1996. Lunar Planet. Sci. XXVII. Abstract #1748.). Away from the three main lobes are numerous outliers of MFF materials. These have mainly been reported in the northern lowlands regions (Keszthelyi, L., Jaeger, W.L., and HiRISE team, 2008. Lunar Planet. Sci. XXXIX. Abstract #2420.) but few studies have examined the possibility of MFF outliers on high ground south of the dichotomy boundary. We have searched Mars Orbiter Camera Narrow Angle (MOC NA) images for outliers in this region. Our observations show that there are many MFF outliers on the southern highlands. The characteristics of the outliers indicate materials which overlie the underlying terrain for they appear widely in dips, craters and topographic lows. The surfaces are typified by yardang fields and have a similar patchy and discontinuous nature to materials of the upper member of the MFF. Most have consistent lineation orientations across the wider area which match the dominant orientation of yardangs in the main MFF outcrops. Furthermore, elevation data shows that the maximum, minimum and mean elevations of these newly discovered outliers are closest to those of the upper member of the MFF. We therefore conclude that these deposits are MFF outliers and that they probably represent remnant upper member material. We suggest that there might be two possible explanations for these outliers: (1) the MFF had a much greater pre-erosional extent than previously estimated, or (2) materials from the main outcrops were eroded and then blown south to accrue in the highland areas, where they were subsequently reworked. We suggest that the topography of the region favors the first option. We outline an 'overflowing' layer-cake deposition model, in which layers of sediment stacked up against the dichotomy boundary until they reached the topographic level of the highlands. Further materials (that went onto become upper-member MFF material and outliers) were then deposited across a wider area, including south of the dichotomy boundary. Severe erosion subsequently removed much of this material. Author Affiliation: (a) Planetary and Space Science Research Institute, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK (b) Dept. of Earth and Environmental Sciences, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK (c) University College London, Department of Space & Climate Physics, Mullard Space Science Laboratory, Holmbury St. Mary, Dorking RH5 6NT, UK Article History: Received 18 January 2010; Revised 21 April 2010; Accepted 21 April 2010

Published
2010

9. Sorted stone circles in Elysium Planitia, Mars: Implications for recent martian climate

Author

Balme, M.R., Gallagher, C.J., Page, D.P., Murray, J.B., and Muller, J.-P.

Subjects
Planetary meteorology, Geography, Mars (Planet), Climate, Lunar geology, Landforms, Environmental sciences, Astronomy, Earth sciences
Abstract

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.icarus.2008.11.010 Byline: M.R. Balme (a)(b), C.J. Gallagher (c), D.P. Page (d), J.B. Murray (a), J.-P. Muller (e) Keywords: Mars; Mars; surface; Mars; climate; Geological processes Abstract: We have found sorted stone circles and polygons near the equator of Mars, using new 25 cm/pixel NASA HiRISE (High Resolution Imaging Science Experiment) images. The sorted circles occur in geologically recent catastrophic flood deposits in the equatorial Elysium Planitia region, and are diagnostic of periglacial processes: sorted polygons do not form from volcanic activity, as has been suggested for non-sorted polygons in this region. These landforms indicate that (i) a long-lived, geologically recent, active cryoturbation layer of ground ice was present in the regolith, (ii) there was some degree of freeze-thaw, and thus (iii) there were sustained period(s), likely within the last 10 Ma, in which the martian climate was 40 to 60 K warmer than current models predict. Author Affiliation: (a) Department of Earth and Environmental Sciences, the Open University, Walton Hall, Milton Keynes, MK7 6AA, UK (b) The Planetary Science Institute, 1700 East Fort Lowell, Suite 106, Tucson, AZ 85719, USA (c) University College Dublin School of Geography, Planning and Environmental Policy, University College Dublin, Belfield, Dublin 4, Ireland (d) Planetary and Space Science Research Institute, the Open University, Walton Hall, Milton Keynes, MK7 6AA, UK (e) University College London, Department of Space & Climate Physics, Mullard Space Science Laboratory, Holmbury St. Mary, Dorking, RH5 6NT, UK Article History: Received 28 July 2008; Revised 24 September 2008; Accepted 3 November 2008

Published
2009

15. Rational design of femtomolar inhibitors of isoleucyl tRNA synthetase from a binding model for pseudomonic acid-A

Author

Brown, Murray J.B., Mensah, Lucy M., Doyle, Michael L., Broom, Nigel J.P., Osbourne, Neal, Forrest, Andrew K., Richardson, Christine M., O'Hanlon, Peter J., and Pope, Andrew J.

Subjects
Biochemistry -- Research, Transfer RNA -- Research, Acids -- Research, Mupirocin -- Research, Biological sciences, Chemistry
Abstract

Research has been conducted on the IleRS inhibitors. The design and characterization of these inhibitors are discussed.

Published
2000

20. Repositioning of a domain in a modular polyketide synthase to promote specific chain cleavage

Author

Cortes, Jesus, Wiesmann, Kirsten E.H., Roberts, Gareth A., Brown, Murray J.B., Staunton, James, and Leadlay, Peter F.

Subjects
Biosynthesis -- Research -- Genetic aspects, Streptomyces -- Genetic aspects -- Research, Science and technology, Genetic aspects, Research
Abstract

Macrocyclic polyketides exhibit an impressive range of medically useful activities, and there is great interest in manipulating the genes that govern their synthesis. The 6-deoxyerythronolide B synthase (DEBS) of Saccharopolyspora erythraea, which synthesizes the aglycone core of the antibiotic erythromycin A, has been modified by repositioning of a chain-terminating cyclase domain to the carboxyl-terminus of DEBS1, the multienzyme that catalyzes the first two rounds of polyketide chain extension. The resulting mutant markedly accelerates formation of the predicted triketide lactone, compared to a control in which the repositioned domain is inactive. Repositioning of the cyclase should be generally useful for redirecting polyketide synthesis to obtain polyketides of specified chain lengths., Complex polyketides are natural products, found predominantly in Streptomyces and related filamentous bacteria, that exhibit an impressive range of antibiotic, anticancer, antiparasite, and immunosuppressant activities. Despite their apparent structural diversity, [...]

Published
1995

30. HRSC: High Resolution Stereo Camera

Author

Neukum, G., Jaumann, R., Basilevsky, A.T., Dumke, A., van Gasselt, S., Giese, B., Hauber, E., Head, J.W., Heipke, C., Hoekzema, N., Hoffmann, H., Greeley, R., Gwinner, K., Kirk, R.L., Markiewicz, W., McCord, T.B., Michael, G., Muller, J.-P., Murray, J.B., Oberst, J., Pinet, P., Pischel, R., Roatsch, T., Scholten, F., Willner, K., HRSC Co-Investigator Team, and HRSC Associates

Subjects
HRSC, geology, Mars, Mars Express
Published
2009

31. Crystal structure of the bacterial ribosomal decoding site complexed with amikacin containing the gamma-amino-alpha-hydroxybutyryl (haba) group

Author

Kondo, J., Francois, B., Russel, R.J., Murray, J.B., Westhof, E., Martin, Isabelle, Architecture et réactivité de l'ARN (ARN), and Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Published
2006

37. A Volcanotectonic Survey of Ascraeus Mons, Mars

Author

Byrne, P.K., Van Wyk de Vries, B., Murray, J.B., Troll, Valentin, Byrne, P.K., Van Wyk de Vries, B., Murray, J.B., and Troll, Valentin

Abstract

Ascraeus Mons is one of the largest volcanoes on Mars. It is replete with well-preserved features that can be used to understand its volcanotectonic evolution. Previous studies of this volcano focused on specific features, and were limited by the quality and coverage of contemporary data. Our objective is to review and enhance the existing developmental model for Ascraeus by considering all endogenic surface features on the volcano. We surveyed the volcano's caldera complex, flank terraces, pit structures, sinuous rilles, arcuate grabens, and small vents. We report the spatial and temporal distributions of these features, appraise their proposed formation mechanisms in light of our mapping results, and propose a detailed geological history for Ascraeus Mons. An initial shield-building phase was followed by the formation of a summit caldera complex and small parasitic cones, while compression due to flexure of the supporting basement led to extensive terracing of the shield flanks. An eruptive hiatus followed, ending with the construction of expansive rift aprons to the northeast and southwest. Against later, extensive flank resurfacing in the late Amazonian, continued flexure formed arcuate grabens concentric to the edifice. Localized eruption and surface flow of a fluid agent (lava and/or water) from within the volcano then produced a population of rilles on the lower flanks. Finally, in a change of flank tectonic regime from compression to extension, pit crater chains and troughs developed on the main shield and rift aprons, eventually coalescing to form large embayments at the northeast and southwest base of the volcano.

Published
2011
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40. DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION

Author

Potter, A., primary, Oldfield, V., additional, Nunns, C., additional, Fromont, C., additional, Ray, S., additional, Northfield, C.J., additional, Bryant, C.J., additional, Scrace, S.F., additional, Robinson, D., additional, Matossova, N., additional, Baker, L., additional, Dokurno, P., additional, Surgenor, A.E., additional, Davis, B.E., additional, Richardson, C.M., additional, Murray, J.B., additional, and Moore, J.D., additional

Published
2011
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41. The origin of Phobos' grooves and crater chains

Author

Murray, J.B.(1), Rothery, D.A.(1), Thornhill, G.D.(1), Muller, J.-P. (2), Iliffe, J.C.(2), Day, T.(2), and Cook, A.C.

Subjects
Phobos, crater chains, photoclinometry, grooves
Published
1994

42. Discovery of cell-active phenyl-imidazole Pin1 inhibitors by structure-guided fragment evolution

Author

Potter, A., primary, Oldfield, V., additional, Nunns, C., additional, Fromont, C., additional, Ray, S., additional, Northfield, C.J., additional, Bryant, C.J., additional, Scrace, S.F., additional, Robinson, D., additional, Matossova, N., additional, Baker, L., additional, Dokurno, P., additional, Surgenor, A.E., additional, Davis, B.E., additional, Richardson, C.M., additional, Murray, J.B., additional, and Moore, J.D., additional

Published
2010
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45. Crystal Structures of Hsc70/Bag1 in Complex with Small Molecule Inhibitors

Author

Williamson, D.S., primary, Borgognoni, J., additional, Clay, A., additional, Daniels, Z., additional, Dokurno, P., additional, Drysdale, M.J., additional, Foloppe, N., additional, Francis, G.L., additional, Graham, C.J., additional, Howes, R., additional, Macias, A.T., additional, Murray, J.B., additional, Parsons, R., additional, Shaw, T., additional, Surgenor, A.E., additional, Terry, L., additional, Wang, Y., additional, Wood, M., additional, and Massey, A.J., additional

Published
2009
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46. Crystal Structure of Hsc70/Bag1 in complex with ATP

Author

Williamson, D.S., primary, Borgognoni, J., additional, Clay, A., additional, Daniels, Z., additional, Dokurno, P., additional, Drysdale, M.J., additional, Foloppe, N., additional, Francis, G.L., additional, Graham, C.J., additional, Howes, R., additional, Macias, A.T., additional, Murray, J.B., additional, Parsons, R., additional, Shaw, T., additional, Surgenor, A.E., additional, Terry, L., additional, Wang, Y., additional, Wood, M., additional, and Massey, A.J., additional

Published
2009
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49. Asite RNA + designer antibiotic

Author

Murray, J.B., primary, Meroueh, S.O., additional, Russell, R.J., additional, Lentzen, G., additional, Haddad, J., additional, and Mobashery, S., additional

Published
2006
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