| Section on Molecular Signal Transduction | |||
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RESEARCH This Unit studies the spatial and temporal organization of intracellular signals that are initiated by stimulation of cell surface receptors by hormones and neurotransmitters. Eukaryotic cells contain a great variety of cell surface receptors through which they receive signals from their environment or from other cells. Transmission of extracellular signals to the cell interior is based on receptor-induced recruitment and assembly of proteins into signaling complexes at the inner leaflet of the plasma membrane. It is being increasingly recognized that cells impose temporal and spatial constraints on the various signaling cascades to ensure signal specificity. Mutations that affect the cellular distribution of regulatory molecules can lead to loss of function, as well as to the development of malignancies. Our
research addresses the nature of the molecular determinants which
underlie important protein-protein and protein-lipid interactions
that are critical for proper localization of signaling molecules.
Most signaling proteins have a modular structure Using
this approach, we have utilized GFP fusion proteins that specifically
recognize the various forms of inositol phosholipids to study the
cellular compartments in which changes in these lipids take place,
and to investigate the manner in which such inositide lipid changes
regulate specific cellular processes. Other work in the Unit has been focused on the role of phosphatidylinositol (PI) 4-kinase enzymes in cellular signaling, following the isolation and molecular cloning of two of these proteins from bovine adrenal and brain in this laboartory. These enzymes are type-III PI 4-kinases, and although both catalyze the same reaction, namely the synthesis of phosphatidylinositol (PI) 4-phosphate, they show distinct subcellular distributions and assume non-redundant functions. Phosphoinositides are involved in almost all aspects of cellular functions in which cellular membranes are remodeled, such as exocytosis, endocytosis, and vesicular trafficking. A combination of research tools to follow inositide dynamics and those that alter the function(s) of the distinct PI 4-kinases will help to define the role of these enzymes at specific signaling steps within the cell. It is also the aim of this laboratory to design methods for the screening of small molecules that would interrupt protein-inositide interactions and could be used as specific inhibitors of inositide-regulated signaling steps. SECTION CHIEF Tamas
Balla received his M.D. degree from the Semmelweis University School
of Medicine, Budapest, Hungary in 1979. He was Assistant Professor
in the Department of Physiology at Semmelweis, working in the laboratory
of Andras Spat, and received his Ph.D. from the Hungarian National
Academy of Science in 1987. He was a post-doctoral fellow in the laboratory
of Kevin J. Catt, at the ERRB of NICHD from 1985-87 and returned to
the NIH in 1989. He is currently Head of the Unit of Molecular Signal
Transduction. Contact Information Tamas
Balla, M.D., Ph.D
PERSONNEL Personnel: ·
Andras Balla, M.D., Ph.D., Bldg. 49; Rm. 6C-56; tel: 301-402-5724;
e-mail: ballaa@mail.nih.gov Collaborators: ·
Dr. Julie Donaldson, Laboratory of Cell Biology, National Heart
Lung and Blood Institute, National Institutes of Health, Bethesda,
MD Former Postdoctoral Fellows: ·
Tzvetanka Bondeva, Ph.D., Research Unit Molecular Cell Biology,
Department of Biology-Pharmacology, Friedrich-Schiller University,
Jena, Germany
BIBLIOGRAPHY Brown FD, Rozelle AL, Yin HL, Balla T, Donaldson JG. (2001) Phosphatidylinositol 4,5-bisphosphate and Arf6-regulated membrane traffic. J Cell Biol. 154(5):1007-17. Zhao X, Varnai P, Tuymetova G, Balla A, Toth ZE, Oker-Blom C, Roder J, Jeromin A, Balla T. (2001) Interaction of neuronal calcium sensor-1 (NCS-1) with phosphatidylinositol 4-kinase beta stimulates lipid kinase activity and affects membrane trafficking in COS-7 cells. J Biol Chem. 276(43):40183-9. Zhou X, Jiang G, Zhao A, Bondeva T, Hirszel P, Balla T. (2001). Inhibition of Na, K-ATPase activates PI3 kinase and inhibits apoptosis in LLC-PK1 cells. Biochem Biophys Res Commun. 285(1):46-51. Marshall JG, Booth JW, Stambolic V, Mak T, Balla T, Schreiber AD, Meyer T, Grinstein S. (2001) Restricted accumulation of phosphatidylinositol 3-kinase products in a plasmalemmal subdomain during Fc gamma receptor-mediated phagocytosis. J Cell Biol. 153(7):1369-80. Balla T. (2001) Pharmacology of phosphoinositides, regulators of multiple cellular functions. Curr Pharm Des. Apr;7(6):475-507. Van der Wahl J, Habets R, Varnai P, Balla T, Jalink K (2001) Monitoring phospholpiase C activation kinetics by FRET . J. Biol. Chem. 276(18):15337-44. Balla T, Bondeva T, Varnai P (2000) How accurately can we image inositol lipids in living cells? Trends Pharmacol. Sci. 21: 238-241. Aharonovitz O, Zaun HC, Balla T, York JD, Orlowski J, Grinstein S (2000) Intracellular pH regulation by Na+/H+ exchange requires phosphatidylinositol 4,5-bisphosphate. J. Cell Biol. 150: 213-24 (2000) Zhao X-H, Bondeva T, Balla T (2000) Characterization of a recombinant phosphatidylinositol 4-kinase beta reveals auto- and heterophosphorylation of the enzyme. J. Biol. Chem. 275: 14642-14648. Holz RW, Hlubek MD, Sorensen SD, Fisher SK, Balla T, Ozaki S, Prestwich GD, Stuenkel EL, Bittner MA. (2000) A pleckstrin homology domain specific for phosphatidylinositol 4, 5-bisphosphate (PtdIns-4,5-P2) and fused to green fluorescent protein identifies plasma membrane PtdIns-4,5-P2 as being important in exocytosis. J Biol Chem. 275:17878-85. Servant G, Weiner OD, Herzmark P, Balla T, Sedat JW, Bourne, HR (2000) Neutrophil chemotaxis: Polarized signals require Rho GTPases. Science, 287: 1037-1040 Zolyomi A, Zhao X-H, Downing GJ, Balla, T (2000) Localization of two distinct phosphatidylinositol 4-kinase mRNAs in the rat. Am. J. Physiol. 278: C914-C920 Várnai P, Rother K, Balla T (1999) Phosphatidylinositol 3-kinase-dependent membrane association of the Bruton's tyrosine kinase pleckstrin-homology domain visualized in single living cells. J. Biol. Chem., 274: 10983-9 Balla T (1998) Phosphatidylinositol 4-kinases. Biochim. Biophys. Acta, 436(1-2):69-85. Varnai P, Balla T (1998) Visualization of phosphoinositides that bind pleckstrin homology domains: calcium-induced dynamic changes and relationship to hormone-sensitive phosphoinositide pools. J. Cell Biol. 143: 501-10 Balla T, Downing GJ, Jaffe H, Kim S, Zolyomi A, Catt KJ. (1997) Identification and molecular cloning of wortmannin-sensitive type-III phosphatidylinositol 4-kinases from bovine adrenal cortex. J. Biol. Chem. 272: 18358-18366. Downing
GJ, Kim S, Nakanishi S, Catt KJ, Balla T (1996) . Characterization
of a soluble adrenal Rossig L, Zolyomi A, Catt KJ, Balla T (1996) Regulation of angiotensin II-stimulated Ca2+ oscillations by Ca2+ influx mechanisms in adrenal glomerulosa cells. J. Biol. Chem. 271: 22063-22069. Nakanishi S, Catt KJ, Balla T (1995) A wortmannin-sensitive phosphatidylinositol 4-kinase that regulates hormone-sensitive pools of inositolphospholipids. Proc. Natn. Acad. Sci. USA. 92: 5317-5321. |
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