Education

scd
University of Cambridge, 2013
博士
University of London, 1989
嘛
剑桥大学，1982年
M.B.，B.Chir
剑桥大学，1981年

Areas of Interest

Research Interests

质膜纳米结构和信号转导

Research Information

质膜纳米结构和信号转导

My laboratory studies basic mechanisms of mammalian cell signaling, especially the function of Ras proteins. These small GTP binding proteins operate as molecular switches in signal transduction pathways and are present in a mutant, activated state in many human tumors. Understanding the basic biology of Ras has major implications for the development of novel anticancer therapeutics. The laboratory uses advanced live cell imaging, electron microscopy, proteomics and mathematical modeling to study how the Ras membrane anchors cooperate with the G-domain and peptide sequences flanking the anchor to drive lateral segregation into dynamic nanodomains, called nanoclusters. This work has generated new models of how lipidated proteins interact with, and use, the plasma membrane to generate signaling platforms and has revealed how the confinement of signaling complexes in plasma membrane nanodomains regulates the kinetics, sensitivity and fidelity of signal transmission. Our most recent work examines how the H-, N- and K-Ras proteins sort different cohorts of membrane lipids into nanoclusters with distinct compositions. Related projects are focused on characterizing the mechanisms whereby K-Ras, the Ras isoform that is most frequently mutated and activated in human tumors, is transported and maintained on the plasma membrane after posttranslational processing on the endoplasmic reticulum. Insights from these basic scientific programs have been translated into drug discovery programs targeting K-Ras.

Research projects

Molecular mapping of the proteins and lipids of Ras nanoclusters.

电子显微镜可视化和定量表征，以在内质膜上建立RAS纳米簇的高分辨率2D图。

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

Development of inhibitors of K-Ras localization and K-Ras nanoscale organization on the plasma membrane, and evaluation of the ability of these inhibitors to block the growth of K-Ras driven human tumors.

Publications

Publication Information

  • Cho KJ，Van der Hoeven D，Zhou Y，Maekawa M，Ma X，Chen W，Fairn GD和Hancock JF。（2015）。芬迪林抑制酸鞘磷脂酶的抑制作用会耗尽细胞磷脂酰丝氨酸，并将其定位于质膜中的K-RAS。摩尔细胞生物。，11月16日。PII：MCB.00719-15。[EPUB在印刷前]。
  • 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.生物化学。Nov 30. [Epub ahead of print]
  • Prakash P，Hancock JF，Gorfe aa。（2015）。Binding hotspots on K-Ras: consensus ligand binding sites and other reactive regions from probe-based molecular dynamics analysis。Proteins.5月; 83（5）：898-909。doi：10.1002/prot.24786。EPUB 2015 3月25日。
  • Prakash P，周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。Mar 8;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).RAS开关II-II-CASS的特定癌症相关突变通过纳米簇增强增加了肿瘤性。Elife.8月14日; 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和Ladbury J.（2015）。在非刺激条件下的GRB2耗竭抑制PTEN，促进Akt诱导的肿瘤形成，并导致卵巢癌的预后不良。癌基因。7月27日。DOI：10.1038/ONC.2015.279。[EPUB在印刷前]。
  • Zhou Y,Hancock JF。（2015）。RAS纳米簇：多功能脂质信号传导。Biochim Biophys Acta.Apr;1853(4):841-9. doi: 10.1016/j.bbamcr.2014.09.008. Epub 2014 Sep 16.
  • Zhou Y, 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）。膜电位调节质膜磷脂动力学和K-RAS信号传导。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 regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling.J Cell Biol。, 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，Mureev S，Johnston W，Gaus K，Gaus K，Hancock JF, Collins BM, Alexandrov K, Parton RG. (2014). Single molecule analysis reveals self assembly and nanoscale segregation of two distinct cavin subcomplexes on caveolae.Elife。3, e01434.
  • Salim AA, Xiao X, Cho KJ, Piggott AM, Lacey E,Hancock JF，Capon RJ。（2014）。罕见的链霉菌聚酮化合物作为K-RAS定位的调节剂。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，汉考克JF，Du G. (2014). Temporal production of the signaling lipid phosphatidic acid by phospholipase D2 determines the output of ERK signaling in cancer cells.摩尔细胞生物。34, 84-95.
  • Zhou Y,Hancock JF。（2014）。RAS纳米簇。章节：小G蛋白的RAS超家族：生物学和机制（Ed。F.Wittinghofer），纽约州Springer。
  • Zhou Y,Hancock JF。（2014）。RAS纳米簇：多功能脂质的信号平台。Biochim Biophys Acta, [Epub ahead of print Sep16].
  • Zhou Y, Liang H, Rodkey T, Ariotti N, Parton RG,Hancock JF。（2014）。通过脂质介导的RAS纳米簇之间的空间交叉讲道进行信号积分。摩尔细胞生物。34, 862-876.
  • Cho K-J,Hancock JF。（2013）。RAS纳米簇：一种新药物？Small GTPases。4，57-60。
  • Cho K-J，Park JH，Hancock JF。（2013）。Staurosporine: A new tool for studying phosphatidylserine trafficking.Commun Integr 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).酶。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,沃特斯MJ，Hancock JF, Grimmond SM, Muscat GE, Parton RG. (2013). Caveolin-1 Is Necessary for Hepatic Oxidative Lipid Metabolism: Evidence for Crosstalk between Caveolin-1 and Bile Acid Signaling.细胞代表。4，238-47。
  • Gambin Y, Ariotti N, McMahon KA, 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, 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）。雄激素衍生物抑制鸟嘌呤核苷酸交换并消除致癌性RAS功能。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,Hancock JF，Schmandt R，Lu Kh。（2013）。二甲双胍的另一个惊喜：通过K-RAS的新型作用机理影响子宫内膜癌对治疗的反应。Mol Cancer Ther。12，2847-2856。
  • Van der Hoeven D, Cho K-J, Ma X, Chigurupati S, Parton RG,Hancock JF。（2013）。Fendiline抑制K-RAS质膜定位，并阻止K-RAS信号传递。摩尔细胞生物。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）。通过磷脂酶D2对信号传导脂质磷脂酸的时间生产决定了癌细胞中ERK信号传导的输出，Mol and Cell Biol。34 (1), 84-95.
  • Zhou Y, Maxell KN, Sezgin E, Lu M, Liang H,Hancock JF，Dial EJ，Lichtenberger LM，Levental I.（2013）。胆汁酸通过质膜结构域的功能扰动来调节信号传导。J Biol Chem288：35660-70。
  • Cho KJ，Park JH，Piggott AM，Salim AA，Gorfe A，Parton RG，Capon RJ，Lacey E，汉考克JF。（2012）星形孢菌素破坏了磷脂酰丝氨酸的运输，并将RAS蛋白误差误差。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，LooD，Martin S，Murphy S，Black DM，Barry R，Simpson F，Liu L，Pilch PF，Hancock JF，Parat MO，Parton RG。（2012）Caveolol蛋白PTRF/Cavin-1和小窝蛋白1对细胞极化和迁移的共调节。PLoS One。7：E43041。
  • Collins B，Davis MJ，Hancock JF，Parton RG。（2012年）基于结构的小窝林信号传导模型的重新评估：小窝可以通过小窝蛋白 - 蛋白质相互作用调节信号传导？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 inhibitors dysregulate the spatiotemporal dynamics of Ras proteins on the plasma membrane.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,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。
  • Prior IA,Hancock JF。(2012) Ras trafficking, localization and compartmentalized signaling.Semin Cell Dev Biol。23日,145 - 153。
  • Cho K-J，Hill MH，Chigurupati S，Du G，Parton RG，汉考克JF。(2011) Therapeutic levels of the HMG-CoA reductase inhibitor lovastatin activate Ras signaling via phospholipase D2.摩尔细胞生物。31，1110-20。
  • Abankwa D，Gorfe AA，Inder K和Hancock JF。(2010) Membrane orientation and nanodomain localization generate Ras isoform diversity.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，和Plowman SJ。（2010）EGFR激活重塑了质膜脂质环境以诱导纳米簇形成。摩尔细胞生物30, 3795-3804.
  • Crouthamel M, Abankwa D, Zhang L, Dilizio C, Manning DR,Hancock JF和Wedegaertner PB。（2010）。信号传导和影响膜纳米域的分布需要GQ的N末端多性基序。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 Cell Biol190, 675-91.
  • Kholodenko BN,Hancock JF和Kolch W.（2010）。在四个维度上发出信号芭蕾舞。自然Rev Mol细胞生物11，414-426。
  • Rotblat B, Belanis L,Hancock JF，Kloog Y和Plowman SJ。（2010）。H-RAS纳米簇稳定性调节MAPK信号输出的幅度。PLoS One5, e11991.
  • Tian T, Plowman SJ, Parton RG, Kloog Y andHancock JF。（2010）。质膜上K-RAS纳米簇形成的数学建模。Biophys J99，534-543。
  • Zhou Y,Hancock JF和Lichtenberger L。（2010）。非甾体类抗炎药吲哚美辛在混合脂质膜中诱导相的异质性：对其多种生物学作用的潜在影响。PLoS One5, e8811.
  • Zhou Y,Lichtenberger L和Hancock 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,汉考克JF，Pilch PF和Parton RG（2009）。MURC/Cavin-4和Cavin家族成员形成组织特异性的洞穴复合物。J细胞生物，185, 1259-1273.
  • Botelho RJ，Harrison RE，Stone JC，Hancock JF飞利浦先生,Jongstra-Bilen J,梅森D,垂直J,Gold MR, Grinstein S (2009). Localized diacylglycerol-dependent stimulation of Ras and Rap during phagocytosis.J Biol Chem，284，28522-28532。
  • Inder K，Lau C，Loo D，Chaudhary N，Goodall A，Martin S，Jones A，Parton RG，Hill M和Hancock JF（2009）。核素和核仁素调节K-RAS质膜相互作用和MAPK信号转导。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 and Pol A (2009). Hydrophobic and basic domains target proteins to lipid droplets.Traffic, 10, 1785-1801.
  • Kiskowski MA，Hancock JF，Kenworthy AK（2009）。关于使用Ripley的K功能及其衍生物来分析域大小。Biophys J, 97,1095-103.
  • Prior IA,Hancock JF，Henis Y（2009）。RAS酰化，分室化和信号纳米簇。Mol Membr Biol，26、80-92。
  • Puji A，Pike T，Widberg C，Payne E，Harding A，Hancock JF, Gabrielli B (2009). MAPK pathway activation delays G2/M progression by destabilizing CDC25B.J Biol Chem，284，33781-33788。
  • Inder K，Harding A，Philips MR，Parton RG和汉考克JF。(2008) Activation of the MAPK module from different spatial locations generates distinct system outputs.摩尔生物细胞，19，4776-4784
  • Shalom-Feuerstein R，Plowman SJ，Rotblat B，Ariotti N，Tian T，Hancock JF和Kloog Y.（2008）K-RAS纳米簇被过表达的支架蛋白乳糖素-3颠覆。癌症, 68, 6608-6616
  • Harding A and汉考克JF。(2008) Using plasma membrane nanoclusters to build better circuits.Trends Cell Sci，18，364-371
  • Plowman SJ, Ariotti N, Parton RG and汉考克JF。(2008) Electrostatic interactions positively regulate K-Ras nanocluster formation and function.摩尔细胞生物, 28, 4377-4385
  • Abankwa D, Hanzal-Bayer M, Ariotti N, Plowman SJ, Gorfe AA, Parton RG, McCammon JA, and汉考克JF。(2008) A novel switch region regulates H-ras membrane orientation and signal output.embo j, 27, 727-735
  • Belanis L，Plowman SJ，Rotblat B，Hancock JF和Kloog Y. (2008) Galectin-1 is a novel structural component and major regulator of H-ras nanoclusters.摩尔生物细胞，19，1404-1414
  • Hill MH，Bastiani M，Luetterforst R，Kirkham M，Kirkham A，Nixon SJ，Walser P，Abankwa D，Oorschot VMJ，Martin S，Hancock JF和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 and汉考克JF。（2007）质膜纳米开关产生高保真性RAS信号转导。自然细胞生物，9，905-914
  • 汉考克JF。(2007) PA promoted to manager.自然细胞生物, 9, 615-617
  • Abankwa D, Gorfe AA and汉考克JF。（2007）RAS纳米簇：分子结构和组装。Semin Cell Dev Biol，18，599-607
  • 小尼古拉（Nicolau Jr. DV），Hancock JF, Burrage K. (2007) Sources of Anomalous Diffusion on Cell Membranes: A Monte Carlo Study.Biophys J, 92, 1975-1987
  • 汉考克JF。（2006）脂筏：仅从简单的角度出发。自然Rev Mol细胞生物，7，456-462。