University of Pittsburgh Department of Cell Biology
  • Research

    Every single one of our 40 trillion cells must execute an intricate yet precise molecular choreography at its surface membrane. In this way cells synchronize the uptake of nutrients, processing of signals, building of tissues and even triggering the cells’ own demise. Viewed from such a perspective, most diseases that affect the human body are intriguing because they influence only some of these processes, leaving most unperturbed. Consider a cancer cell; it grows uncontrollably and refuses to die due to aberrant signaling mechanisms, yet maintains the capacity to move and nourish itself. Our lab studies a vital family of lipid molecules, the inositol lipids, that normally regulate and coordinate these essential membrane processes. We uncover fundamental new mechanisms that explain how these molecules choreograph membrane function, and – crucially – why some lipid-dependent functions fail in disease, while others are spared. To do this, we develop novel probes and tools using genetic engineering to probe living cell membranes in real time under the microscope. Some current projects include:

    • Mapping the molecular organization of the membrane during normal physiology, and how this changes during oncogenic signaling. We use cutting-edge super-resolution and single molecule imaging approaches to accomplish this. We aim to identify the composition of specific molecular complexes that might be targetable with drugs to disrupt oncogenic signaling.
    • Working out the detailed control mechanisms for lipid signaling in smooth muscle cells, and how this is altered during diseases like hypertension and asthma. A combination of chemical and molecular genetics is used here, along with traditional biochemical and novel single-cell assays. We aim to identify new drug targets to control smooth muscle cell contraction in these diseases.
    • Identifying how aberrant accumulation of signaling lipids leads to targeted disruption of cellular function, and what mechanisms could be brought into play to correct this. The aim is to apply this knowledge to genetic diseases that cause aberrant lipid accumulation, leading to diseases as diverse as neurodegeneration and polycystic kidney disease. We apply a range of state-ofthe- art gene editing and novel chemical genetic tools to study this problem at the single cell level.
  • Publications

    1. Burke JE, Triscott J, Emerling BM, Hammond GRV. Beyond PI3Ks: targeting phosphoinositide kinases in disease.. Nat Rev Drug Discov. 2023 May;22(5):357-386. doi: 10.1038/s41573-022-00582-5. PubMed PMID: 36376561;
    2. Goulden BD, Pacheco J, Dull A, Zewe JP, Deiters A, Hammond GRV. A high-avidity biosensor reveals plasma membrane PI(3,4)P<sub>2</sub> is predominantly a class I PI3K signaling product.. J Cell Biol. 2018 Dec 27;():. pii: jcb.201809026. doi: 10.1083/jcb.201809026. PubMed PMID: 30591513;
    3. Hammond GRV. DepHining membrane identity.. J Cell Biol. 2018 Jan 2;217(1):19-20. doi: 10.1083/jcb.201711134. PubMed PMID: 29233864;
    4. Hammond GR, Balla T. Polyphosphoinositide binding domains: Key to inositol lipid biology. Biochim Biophys Acta. 2015 Feb 27. pii: S1388-1981(15)00061-X. doi: 10.1016/j.bbalip.2015.02.013. [Epub ahead of print] Review. [link]
    5. Hammond GR, Machner MP, Balla T. A novel probe for phosphatidylinositol 4-phosphate reveals multiple pools beyond the Golgi. J Cell Biol. 2014 Apr 14;205(1):113-26. doi: 10.1083/jcb.201312072. Epub 2014 Apr 7. [link]
    6. Bojjireddy N, Botyanszki J, Hammond G, Creech D, Peterson R, Kemp DC, Snead M, Brown R, Morrison A, Wilson S, Harrison S, Moore C, Balla T. Pharmacological and genetic targeting of the PI4KA enzyme reveals its important role in maintaining plasma membrane phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate levels. J Biol Chem. 2014 Feb 28;289(9):6120-32. doi: 10.1074/jbc.M113.531426. Epub 2014 Jan 10. [link]
    7. Lukacs V, Yudin Y, Hammond GR, Sharma E, Fukami K, Rohacs T. Distinctive changes in plasma membrane phosphoinositides underlie differential regulation of TRPV1 in nociceptive neurons. J Neurosci. 2013 Jul 10;33(28):11451-63. doi: 10.1523/JNEUROSCI.5637-12.2013. [link]
    8. Kruse M, Hammond GR, Hille B. Regulation of voltage-gated potassium channels by PI(4,5)P2. J Gen Physiol. 2012 Aug;140(2):189-205. doi: 10.1085/jgp.201210806. [link]
    9. Hammond GR, Fischer MJ, Anderson KE, Holdich J, Koteci A, Balla T, Irvine RF. PI4P and PI(4,5)P2 are essential but independent lipid determinants of membrane identity. Science. 2012 Aug 10;337(6095):727-30. doi: 10.1126/science.1222483. Epub 2012 Jun 21. [link]
    10. Ayling LJ, Briddon SJ, Halls ML, Hammond GR, Vaca L, Pacheco J, Hill SJ, Cooper DM. Adenylyl cyclase AC8 directly controls its micro-environment by recruiting the actin cytoskeleton in a cholesterol-rich milieu. J Cell Sci. 2012 Feb 15;125(Pt 4):869-86. doi: 10.1242/jcs.091090. Epub 2012 Mar 7. [link]
    11. Delint-Ramirez I, Willoughby D, Hammond GV, Ayling LJ, Cooper DM. Palmitoylation targets AKAP79 protein to lipid rafts and promotes its regulation of calcium-sensitive adenylyl cyclase type 8. J Biol Chem. 2011 Sep 23;286(38):32962-75. doi: 10.1074/jbc.M111.243899. Epub 2011 Jul 19. [link]
    12. Lindner M, Leitner MG, Halaszovich CR, Hammond GR, Oliver D. Probing the regulation of TASK potassium channels by PI4,5P₂ with switchable phosphoinositide phosphatases. J Physiol. 2011 Jul 1;589(Pt 13):3149-62. doi: 10.1113/jphysiol.2011.208983. Epub 2011 May 3. [link]
    13. Hammond GR, Schiavo G, Irvine RF. Immunocytochemical techniques reveal multiple, distinct cellular pools of PtdIns4P and PtdIns(4,5)P(2). Biochem J. 2009 Jul 29;422(1):23-35. doi: 10.1042/BJ20090428. [link]
    14. Hammond GR, Sim Y, Lagnado L, Irvine RF. Reversible binding and rapid diffusion of proteins in complex with inositol lipids serves to coordinate free movement with spatial information. J Cell Biol. 2009 Jan 26;184(2):297-308. doi: 10.1083/jcb.200809073. Epub 2009 Jan 19. [link]
    15. Hammond GR, Dove SK, Nicol A, Pinxteren JA, Zicha D, Schiavo G. Elimination of plasma membrane phosphatidylinositol (4,5)-bisphosphate is required for exocytosis from mast cells. J Cell Sci. 2006 May 15;119(Pt 10):2084-94. [link]
    16. Meunier FA, Osborne SL, Hammond GR, Cooke FT, Parker PJ, Domin J, Schiavo G. Phosphatidylinositol 3-kinase C2alpha is essential for ATP-dependent priming of neurosecretory granule exocytosis. Mol Biol Cell. 2005 Oct;16(10):4841-51. Epub 2005 Jul 29. [link]


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