Education

ScD
University of Cambridge, 2013
Ph.D
伦敦大学，1989年
M.A
University of Cambridge, 1982
M.B., B.Chir
University of Cambridge, 1981

Areas of Interest

beplay苹果手机能用吗研究兴趣

Plasma Membrane Nanostructure and Signal Transduction

Research Information

Plasma Membrane Nanostructure and Signal Transduction

我的实验室研究哺乳动物细胞信号传导的基本机制，尤其是RAS蛋白的功能。这些小的GTP结合蛋白作为信号转导途径中的分子开关起作用，并且存在于许多人类肿瘤中的突变体激活状态。了解RAS的基本生物学对新型抗癌治疗剂的发展具有重大影响。实验室使用先进的活细胞成像，电子显微镜，蛋白质组学和数学建模来研究RAS锚固如何与G-域和肽序列合作，将锚固侧面的肽序列置于锚固侧面，以将侧向分离驱动到动态纳米缺晶，称为纳米升高。这项工作已经生成了新的模型，说明脂质蛋白如何与质膜相互作用并使用质膜生成信号平台，并揭示了质膜纳米域中信号复合物的限制如何调节信号传输的动力学，敏感性和忠诚度。我们最近的工作研究了H-，N-和K-RAS蛋白如何将不同的膜脂质组分为具有不同组成的纳米簇。相关项目的重点是表征该机制，在该机制中，在人肿瘤中最常突变和激活的RAS同工型K-RAS在内质网上翻译后处理后，在质膜上运输和维持。这些基本科学计划的见解已转化为针对K-RAS的药物发现计划。

beplay苹果手机能用吗研究项目

Molecular mapping of the proteins and lipids of Ras nanoclusters.

电子显微可视化和quantitative characterization to build up a high-resolution 2D map of Ras nanoclusters on the inner plasma membrane.

Characterization of the mechanism(s) whereby K-Ras is targeted to, organized and regulated on the plasma membrane.

在质膜上开发K-RAS定位和K-RAS纳米级组织的抑制剂，并评估这些抑制剂阻止K-RAS驱动的人类肿瘤生长的能力。

出版物

出版信息

  • Cho KJ, van der Hoeven D, Zhou Y, Maekawa M, Ma X, Chen W, Fairn GD andHancock JF。(2015).Inhibition of acid sphingomyelinase by fendiline depletes cellular phosphatidylserine and mis-localizes K-Ras from the plasma membrane.Mol Cell Biol., Nov 16. pii: MCB.00719-15. [Epub ahead of print].
  • Najumudeen AK, Posada IMD, Lectez B, Zhou Y, Landor S, Fallarero A, Vuorela P,Hancock JF, Abankwa D. (2015).Phenotypic screening identifies protein synthesis inhibitors as H-ras nanocluster dependent tumor growth inducers.Biochemistry。Nov 30. [Epub ahead of print]
  • Prakash P,Hancock JF, Gorfe AA。(2015).K-RAS上的结合热点：基于探针的分子动力学分析的共有配体结合位点和其他反应区域。Proteins.May;83(5):898-909. doi: 10.1002/prot.24786. Epub 2015 Mar 25.
  • Prakash P, Zhou Y, Liang H,Hancock JF, Gorfe AA。(2016).Oncogenic K-Ras Binds to an Anionic Membrane in Two Distinct Orientations: A Molecular Dynamics Analysis.Biophys j。3月8日； 110（5）：1125-38。PMID：26958889。
  • Solman S, Ligabue A, Blazevits O, Jaiswal A, Zhou Y, Liang H, Lectez B, Kopra K, Guzman C, Harma H,Hancock JF, Aittokallio T and Abankwa D (2015).Specific cancer associated mutations in the switch III-region of Ras increase tumorigenicity by nanocluster augmentation。Elife。Aug 14;4. doi: 10.7554/eLife.08905.
  • Timsah Z, Ahmed Z, Ivan C, Berrout J, Gagea M, Zhou Y, Pena G, Hu X, Vallien C, Kingsley C, Lu Y,Hancock JF, Liu J, Gladden A, Mills G, Lopez-Berestein G, Hung MC, Sood A, Bogdanov M and Ladbury J. (2015).Grb2 depletion under non-stimulated conditions inhibits PTEN, promotes Akt-induced tumor formation and contributes to poor prognosis in ovarian cancer.Oncogene.Jul 27. doi: 10.1038/onc.2015.279. [Epub ahead of print].
  • 周，Hancock JF。(2015).Ras nanoclusters: versatile lipid-based signaling。Biochim Biophys Acta。Apr;1853(4):841-9. doi: 10.1016/j.bbamcr.2014.09.008. Epub 2014 Sep 16.
  • 周，Wong CO, Cho KJ, van der Hoeven D, Liang H, Thakur DP, Luo J, Babic M, Zinsmaier KE, Zhu MX, Hu H, Venkatachalam K andHancock JF。(2015).Membrane potential modulates plasma membrane phospholipid dynamics and K-Ras signaling。Science.Aug 21;349(6250):873-6. doi: 10.1126/science.aaa5619.
  • Ariotti N, Fernández-Rojo MA, Zhou Y, Hill MM, Rodkey T, Inder K,Hancock JF，Parton RG。（2014）。Caveolae调节质膜的纳米级组织以远程控制RAS信号。J细胞生物。, 204, 777-792.
  • Gambin Y, Ariotti N, McMahon K, Bastiani M, Sierecki E, Kovtun O, Magenau A, Jung W, Okano S, Zhou Y, Leneva N, Mureev S, Johnston W, Gaus K,Hancock JF，Collins BM，Alexandrov K，Parton RG。（2014）。单分子分析揭示了两个小窝上两个不同的卡氏子复合物的自组装和纳米级分离。eLife。3, e01434.
  • Salim AA，小X，Cho KJ，Piggott AM，Lacey E，Hancock JF, Capon RJ. (2014). Rare Streptomyces sp. polyketides as modulators of K-Ras localization.Org Biomol Chem。，12，4872-4878。
  • Salim AS，Cho K-J，Tan L，Quezada M，Lacey E，Hancock JF, Capon RJ. (2014). Rare Streptomyces N-formyl amino-salicylamides inhibit oncogenic K-Ras.Org Lett., 16, 5036-5039.
  • Zhang F, Wang Z, Lu M, Yonekubo Y, Liang X, Zhang Y, Wu P, Zhou Y, Grinstein S,Hancock JF,Du G. (2014). Temporal production of the signaling lipid phosphatidic acid by phospholipase D2 determines the output of ERK signaling in cancer cells.Mol Cell Biol。34，84-95。
  • 周，Hancock JF。（2014）。Ras nanoclusters. Chapter in: Ras superfamily of small G proteins: biology and mechanisms (Ed. F. Wittinghofer) Springer, NY.
  • 周，Hancock JF。（2014）。Ras nanoclusters: versatile lipid-based signaling platforms.Biochim Biophys Acta，[EPUB在印刷9月16日之前。
  • Zhou Y，Liang H，Rodkey T，Ariotti N，Parton RG，Hancock JF。（2014）。Signal integration by lipid-mediated spatial cross talk between Ras nanoclusters.Mol Cell Biol。34, 862-876.
  • Cho K-J,Hancock JF。(2013)。Ras nanoclusters: A new drug target?.小GTPases。4, 57-60.
  • Cho K-J, Park JH,Hancock JF。(2013)。Staurosporine: A new tool for studying phosphatidylserine trafficking.社区Integry Biol。6, e24746.
  • Cho K-J, van der Hoeven D, Hancock JF. (2013). Inhibitors of K-Ras plasma membrane localization. Chapter in: Inhibitors of the Ras Superfamily G-proteins (Ed. F. Tamanoi).The Enzymes。33, 249-265.
  • Fernández-Rojo MA, Gongora M, Fitzsimmons RL, Martel N, Martin SD, Nixon SJ, Brooks AJ, Ikonomopoulou MP, Martin S, Lo HP, Myers SA, Restall C, Ferguson C, Pilch PF, McGee SL, Anderson RL, Waters MJ,Hancock JF，Grimmond SM，Muscat GE，Parton RG。(2013)。Caveolin-1对于肝氧化脂质代谢是必需的：小窝蛋白-1和胆汁酸信号传导之间串扰的证据。Cell Rep。4, 238-47.
  • Gambin Y，Ariotti N，McMahon KA，Bastiani M，Sierecki E，Kovtun O，Magenau A，Jung W，Okano S，Zhou Y，Zhou Y，Leneva N，Mureev S，Mureev S，Johnston W，Johnston W，Gaus K，Gaus K，Hancock JF, Collins BM, Ramaswamy SS, MacLean DM, Gorfe AA, Jayaraman V. (2013). pH induced conformational changes in Acid Sensing Ion Channel.J Biol Chem.288, 35896-35903.
  • Hocker HJ, Cho K-J, Chen C-YK, Rambahal N, Sagineedu SR, Shaari K, Stanslas J,Hancock JF, Gorfe AA。(2013)。Andrographolide衍生品hibit guanine nucleotide exchange and abrogate oncogenic Ras function.Proc Natl Acad Sci U S A. 110，10201-10206.
  • Iglesias DA，Yates MS，Van der Hoeven D，Rodkey TL，Zhang Q，Co nn，Burzawa J，Chigurupati S，Celestino J，Bowser J，Broaddus R，Broaddus R，Hancock JF, Schmandt R, Lu KH. (2013). Another Surprise from Metformin: Novel Mechanism of Action via K-Ras Influences Endometrial Cancer Response to Therapy.Mol Cancer Ther。12, 2847-2856.
  • Van der Hoeven D, Cho K-J, Ma X, Chigurupati S, Parton RG,Hancock JF。(2013)。Fendiline inhibits K-Ras plasma membrane localization and blocks K-Ras signal transmission.Mol Cell Biol。33, 237-251.
  • Zhang F, Wang Z, Lu M, Yonekubo Y, Liang X, Zhang Y, Wu P, Zhou Y, Grinstein S,Hancock JF, Du G. (2013). Temporal production of the signaling lipid phosphatidic acid by phospholipase D2 determines the output of ERK signaling in cancer cells,Mol and Cell Biol。34 (1), 84-95.
  • 周，Maxell KN, Sezgin E, Lu M, Liang H,Hancock JF, Dial EJ, Lichtenberger LM, Levental I. (2013). Bile acids modulate signaling by functional perturbation of plasma membrane domains.J Biol Chem288: 35660-70.
  • Cho KJ, Park JH, Piggott AM, Salim AA, Gorfe A, Parton RG, Capon RJ, Lacey E,Hancock JF.(2012) Staurosporines disrupt phosphatidylserine trafficking and mislocalize Ras proteins.J Biol Chem.287, 43573-43584.
  • Sykes AM, Palstra N, Abankwa D, Hill JM, Skeldal S, Matusica D, Venkatraman P,Hancock JF, Coulson EJ. (2012) The effects of transmembrane sequence and dimerization on cleavage of the p75 neurotrophin receptor by γ-secretase.J Biol Chem.287, 43810-43824.
  • Hill MM, Daud NH, Aung CS, Loo D, Martin S, Murphy S, Black DM, Barry R, Simpson F, Liu L, Pilch PF,Hancock JF, Parat MO, Parton RG. (2012) Co-regulation of cell polarization and migration by caveolar proteins PTRF/cavin-1 and caveolin-1.PLOS ONE。7: e43041.
  • Collins B, Davis MJ,Hancock JF，Parton RG。(2012) Structure-based reassessment of the caveolin signaling model: do caveolae regulate signaling through caveolin-protein interactions?Dev Cell，23，11-20。
  • 曹K-j,Kasai RS, Park J-H, Chigurupati S, Heidorn SJ, van der Hoeven D, Plowman SJ, Kusumi A, Marais R,Hancock JF。（2012）RAF抑制剂失调质膜上RAS蛋白的时空动力学。Curr Biol。22, 945-955.
  • Lanosi J, Li Z,Hancock JF, Gorfe AA。(2012) Organization, dynamics and segregation of Ras nanoclusters in membrane domains.Proc Natl Acad Sci USA.109, 8097-8102.
  • Walser PJ，Ariotti N，Howes M，Ferguson C，Webb R，Schwudke D，Leneva N，Cho KJ，Cooper L，Rae J，Floetenmeyer M，Oorschot VM，Skoglund U，Simons K，Simons K，K，，Simons K，，Hancock JF，Parton RG。(2012) Constitutive formation of caveolae in a bacterium.Cell.150，752-763。
  • 周Y,曹K-j庄稼汉SJ,Hancock JF。(2012) Non-steroidal anti-inflammatory drugs alter the spatiotemporal organization of Ras proteins on the plasma membrane.J Biol Chem.287, 16586-16595.
  • ia，Hancock JF。(2012) Ras trafficking, localization and compartmentalized signaling.Semin Cell Dev Biol.23日,145 - 153。
  • 曹K-j,Hill MH, Chigurupati S, Du G, Parton RG,Hancock JF.(2011) Therapeutic levels of the HMG-CoA reductase inhibitor lovastatin activate Ras signaling via phospholipase D2.Mol Cell Biol.31, 1110-20.
  • Abankwa D, Gorfe AA, Inder K, andHancock JF。（2010）膜方向和纳米域定位产生RAS同工型多样性。Proc Natl Acad Sci USA。107, 1130-1135.
  • Ariotti N, Liang H, Xu Y, ZhangY, Yonekubo Y, Inder K, Du G, Parton RG,Hancock JF, and Plowman SJ. (2010) EGFR activation remodels the plasma membrane lipid environment to induce nanocluster formation.Mol Cell Biol30, 3795-3804.
  • Crouthamel M，Abankwa D，Zhang L，Dilizio C，Manning DR，Hancock JFand Wedegaertner PB. (2010). An N-terminal polybasic motif of Gq is required for signaling and influences membrane nanodomain distribution.Mol Pharmacol78, 767-777.
  • Howes MT, Kirkham M, Riches J, Cortese K, Walser PJ, Simpson F, Hill MM, Jones A, Lundmark R, Lindsay MR, Hernandez-Deviez DJ, Hadzic G, McCluskey A, Bashir R, Liu L, Pilch P, McMahon H, Robinson PJ,Hancock JF, Mayor S and Parton RG. (2010). Clathrin-independent carriers form a high capacity endocytic sorting system at the leading edge of migrating cells.J细胞生物190, 675-91.
  • Kholodenko BN,Hancock JFand Kolch W. (2010). Signalling ballet in four dimensions.Nature Rev Mol Cell Biol11, 414-426.
  • Rotblat B, Belanis L,Hancock JF, Kloog Y and Plowman SJ. (2010). H-Ras nanocluster stability regulates the magnitude of MAPK signal output.PLOS ONE5, e11991.
  • Tian T, Plowman SJ, Parton RG, Kloog Y andHancock JF。(2010). Mathematical modeling of K-Ras nanocluster formation on the plasma membrane.Biophys j99, 534-543.
  • 周，Hancock JFandLichtenberger L。(2010). Nonsteroidal anti-inflammatory drug indomethacin induces phase heterogeneity in mixed lipid membranes: potential implication for its diverse biological actions.PLOS ONE5，E8811。
  • 周，Lichtenberger LandHancock JF。(2010). The anti-inflammatory drug indomethacin alters nanoclustering in synthetic and cell plasma membranes.J Biol Chem285, 35188-35195.
  • Bastiani M, Liu L, Hill MH, Jedrychowski MP, Nixon SJ, Lo HP, Abankwa D, Luetterforst R, Fernandez-Rojo, Breen MR, Steven P, Gygi SP, Vinten J, Walser PJ, North KN,Hancock JF,Pilch PF and Parton RG (2009). MURC/Cavin-4 and cavin family members form tissue-specific caveolar complexes.J细胞生物,185, 1259-1273.
  • Botelho RJ, Harrison RE, Stone JC,Hancock JF，飞利浦MR，Jongstra-Bilen J，Mason D，Plumb J，Gold MR，Grinstein S（2009）。吞噬作用过程中RAS和RAP的局部二酰基甘油依赖性刺激。J Biol Chem,284, 28522-28532.
  • Inder K, Lau C, Loo D, Chaudhary N,Goodall A, Martin S, Jones A, Parton RG, Hill M andHancock JF(2009). Nucleophosmin and nucleolin regulate K-Ras plasma membrane interactions and MAPK signal transduction.J Biol Chem, 284, 28410-28419.
  • Ingelmo-Torres M, González-Moreno E, Kassan A, Hanzal-Bayer M, Tebar F, Herms A, Grewal T,Hancock JF，Enrich C，Bosch M，Gross S，Parton RG和Pol A（2009）。疏水性和基本结构域靶向蛋白质到脂质液滴。交通，10，1785-1801。
  • Kiskowski MA,Hancock JF, Kenworthy AK (2009). On the use of Ripley’s K-function and its derivatives to analyze domain size.Biophys j，97,1095-103。
  • ia，Hancock JF, Henis Y (2009). Ras acylation, compartmentalization and signaling nanoclusters.Mol Membr Biol, 26, 80-92.
  • Puji A, Pike T, Widberg C, Payne E, Harding A,Hancock JF，Gabrielli B（2009）。MAPK途径激活通过破坏CDC25B的稳定来延迟G2/M的进展。J Biol Chem, 284, 33781-33788.
  • Inder K, Harding A, Philips MR, Parton RG andHancock JF.(2008) Activation of the MAPK module from different spatial locations generates distinct system outputs.Mol Biol Cell, 19, 4776-4784
  • Shalom-Feuerstein R, Plowman SJ, Rotblat B, Ariotti N, Tian T,Hancock JFand Kloog Y. (2008) K-Ras nanoclustering is subverted by over-expression of the scaffold protein galectin-3.Cancer Res, 68, 6608-6616
  • Harding A和Hancock JF.（2008）使用质膜纳米簇来建造更好的电路。趋势细胞科学, 18, 364-371
  • Plowman SJ，Ariotti N，Parton RG和Hancock JF.(2008) Electrostatic interactions positively regulate K-Ras nanocluster formation and function.Mol Cell Biol, 28, 4377-4385
  • Abankwa D，Hanzal-Bayer M，Ariotti N，Plowman SJ，Gorfe AA，Parton RG，McCammon JA和Hancock JF.（2008）一个新的开关区域调节H-RAS膜方向和信号输出。EMBO J, 27, 727-735
  • Belanis L, Plowman SJ, Rotblat B,Hancock JF和Kloog Y.（2008）Galectin-1是H-RAS纳米簇的新型结构成分和主要调节剂。Mol Biol Cell, 19, 1404-1414
  • Hill MH, Bastiani M, Luetterforst R, Kirkham M, Kirkham A, Nixon SJ, Walser P, Abankwa D, Oorschot VMJ, Martin S,Hancock JFand Parton RG. (2008) PTRF, a novel, conserved caveolar coat protein that regulates caveolae formation and function.Cell, 132, 113-124
  • Tian T，Harding A，Inder K，Plowman SJ，Parton RG和Hancock JF.(2007) Plasma membrane nanoswitches generate high-fidelity Ras signal transduction.Nature Cell Biol, 9, 905-914
  • Hancock JF.（2007）PA晋升为经理。Nature Cell Biol, 9, 615-617
  • Abankwa D，Gorfe AA和Hancock JF.(2007) Ras nanoclusters: molecular structure and assembly.Semin Cell Dev Biol, 18, 599-607
  • Nicolau Jr. DV,Hancock JF, Burrage K. (2007) Sources of Anomalous Diffusion on Cell Membranes: A Monte Carlo Study.Biophys j，92，1975-1987
  • Hancock JF.(2006) Lipid rafts: contentious only from simplistic standpoints.Nature Rev Mol Cell Biol, 7, 456-462.