Education

ScD
University of Cambridge, 2013
Ph.D
University of London, 1989
M.A
University of Cambridge, 1982
M.B., B.Chir
University of Cambridge, 1981

Areas of Interests

Research Interests

Plasma Membrane Nanostructure and Signal Transduction

Research Information

Plasma Membrane Nanostructure and Signal Transduction

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.

Electron microscopic visualization and 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.

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

REFERENCES:

  • Cho KJ, van der Hoeven D, Zhou Y, Maekawa M, Ma X, Chen W, Fairn GD and Hancock 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). Binding hotspots on K-Ras: consensus ligand binding sites and other reactive regions from probe-based molecular dynamics analysis. 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. 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). 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].
  • Zhou Y, 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.
  • 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 and Hancock 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 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, Johnston W, 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).  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.
  • Zhou Y, Hancock JF. (2014). Ras nanoclusters. Chapter in: Ras superfamily of small G proteins: biology and mechanisms (Ed. F. Wittinghofer) Springer, NY.
  • Zhou Y, Hancock JF. (2014).  Ras nanoclusters: versatile lipid-based signaling platforms.  Biochim Biophys Acta, [Epub ahead of print Sep16].
  • 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?. 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). 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 Is Necessary for Hepatic Oxidative Lipid Metabolism: Evidence for Crosstalk between Caveolin-1 and Bile Acid Signaling. 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, 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). Andrographolide derivatives inhibit 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, 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.
  • Zhou Y, 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 Chem 288: 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.
  • Cho 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.
  • Zhou Y, Cho K-j, Plowman 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, 145-153.
  • Cho 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, and 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, and Plowman SJ. (2010) EGFR activation remodels the plasma membrane lipid environment to induce nanocluster formation. Mol Cell Biol 30, 3795-3804.
  • Crouthamel M, Abankwa D, Zhang L, Dilizio C, Manning DR, Hancock JF and Wedegaertner PB. (2010). An N-terminal polybasic motif of Gq is required for signaling and influences membrane nanodomain distribution. Mol Pharmacol 78, 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 Biol 190, 675-91.
  • Kholodenko BN, Hancock JF and Kolch W. (2010). Signalling ballet in four dimensions. Nature Rev Mol Cell Biol 11, 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 One 5, e11991.
  • Tian T, Plowman SJ, Parton RG, Kloog Y and Hancock JF. (2010). Mathematical modeling of K-Ras nanocluster formation on the plasma membrane. Biophys J 99, 534-543.
  • Zhou Y, Hancock JF and Lichtenberger L. (2010). Nonsteroidal anti-inflammatory drug indomethacin induces phase heterogeneity in mixed lipid membranes: potential implication for its diverse biological actions. PLoS One 5, e8811.
  • Zhou Y, Lichtenberger L and Hancock JF. (2010). The anti-inflammatory drug indomethacin alters nanoclustering in synthetic and cell plasma membranes. J Biol Chem 285, 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 Cell Biol, 185, 1259-1273.
  • Botelho RJ, Harrison RE, Stone JC, Hancock JF, Philips MR, Jongstra-Bilen J, Mason D, Plumb 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 and Hancock 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 and Pol A (2009). Hydrophobic and basic domains target proteins to lipid droplets. Traffic, 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.
  • Prior 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 pathway activation delays G2/M progression by destabilizing CDC25B. J Biol Chem, 284, 33781-33788.
  • Inder K, Harding A, Philips MR, Parton RG and Hancock 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 JF and Kloog Y. (2008)  K-Ras nanoclustering is subverted by over-expression of the scaffold protein galectin-3. Cancer Res, 68, 6608-6616
  • Harding A and Hancock JF. (2008) Using plasma membrane nanoclusters to build better circuits. Trends Cell Sci,  18, 364-371
  • Plowman SJ, Ariotti N, Parton RG and 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, and Hancock 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 and Kloog Y. (2008) Galectin-1 is a novel structural component and major regulator of H-ras nanoclusters.  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 JF and 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 Hancock JF. (2007) Plasma membrane nanoswitches generate high-fidelity Ras signal transduction.  Nature Cell Biol, 9, 905-914
  • Hancock JF.  (2007) PA promoted to manager. Nature Cell Biol,  9, 615-617
  • Abankwa D, Gorfe AA and 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.