Dr Ewen Gallagher

 

Lymphocyte Signalling

For many years we have known that white blood cells are controlled by complex signalling programs initiated by receptors on their cell surface. Understanding the intricate mechanisms that comprise the signal transduction pathways in white blood cells (lymphocytes) is of great importance to modern biomedical research. These control many vital cellular responses, encompassing cell death to proliferation, and are also found to signal erroneously in many autoimmune diseases, for example rheumatoid arthritis.

Several lymphocyte receptors can relay these messages by the protein kinase MEK kinase 1 (MEKK1) to activate the enzyme Itch, which then labels target proteins inside cells with a modification called ubiquitin (Ub), leading to their degradation or alteration of cellular function.  Itch integrates upstream signals from receptors to become activated and can then differentially regulate numerous target proteins important for the biology of white blood cells depending on the specific receptor signalling programs initiated. Some of the fundamental biological processes that are regulated by Itch include the decision of cells to die or differentiate further as part of the immune response. My research defines mechanisms of Itch regulation at the molecular level and this will lead to a better understanding of white blood cell biology, and long-term may facilitate the development of new therapeutic approaches to modify the immune system to combat disease.

My research aims to understand the mechanisms of signal transduction mediated by the kinase enzymes TGF-beta-activated kinase 1 (TAK1) and MEKK1 in lymphocytes from the important Tumor Necrosis Family of receptors (TNFRs). TNFRs relay information from the surface of lymphocytes to the gene expression machinery and other intracellular targets for signalling to control fundamental cellular decisions, for example: survival, apoptosis, antibody secretion and migration.

Publications:

Enzler T, Chang X, Facchinetti V, Melino G, Karin M, Su B, Gallagher E.  MEKK1 binds HECT E3 ligase Itch by its amino-terminal RING motif to regulate Th2 cytokine gene expression.   J Immunol. 2009 Sep 15;183(6):3831-8. Epub 2009 Aug 26.  Publisher website
 
Matsuzawa A, Tseng PH, Vallabhapurapu S, Luo JL, Zhang W, Wang H, Vignali DA, Gallagher E, Karin M.  Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex.  Science. 2008 Aug 1;321(5889):663-8. Epub 2008 Jul 17.  Publsiher website
 
Gallagher E, Enzler T, Matsuzawa A, Anzelon-Mills A, Otero D, Holzer R, Janssen E, Gao M, Karin, M.  Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production. Nat Immunol. 2007 Jan;8(1):57-63. Epub 2006 Dec 3.  Publisher website