Professor and Head, Department of Immunology
Post Doctoral Fellowship, University of Washington (1997-2000)
Ph.D., University of Toronto (1997)
B.Sc., University of Saskatchewan (1992)
Department of Immunology
University of Manitoba
Rady Faculty of Health Sciences
Max Rady College of Medicine
473 Apotex Centre
750 McDermot Avenue
Phone: (204) 272-3082
Lab: (204) 789-3965
Fax: (204) 789-3921
Our lab carries out discovery research focusing primarily on the regulation B lymphocyte responses. B cells are the subset of white blood cells that produce antibodies, which play critical roles in vaccine responses and protection from infections. However, when not appropriately regulated, B cell activation and production of antibodies can lead to destructive effects including chronic diseases such as lupus erythematosus, rheumatoid arthritis or multiple sclerosis. In addition, defective regulation of B cell activation processes can lead to continual cell division, causing B cell leukemia or lymphoma.
B cell responses are controlled by cell surface receptors that allow them to sense the presence of antigens, tissue damage and other activated cells. Signals from these receptors determine whether individual B lymphocytes divide to produce more copies of themselves, differentiate to become antibody-secreting factories or die by cell suicide. Cell surface receptors deliver signals to the interior of the cell through a network of signal transduction proteins. We are characterizing a specific subset of B lymphocyte signal transduction proteins and determining how these proteins fit into the network of signals that regulate cell survival, metabolic activity, proliferation and migration. The specific focus of the lab is on the phosphoinositide 3-kinase pathway (PI3K), including studies on PI 3-kinase delta and gamma isoforms, PI phosphatases SHIP, INPP4 and PTEN and PI-binding proteins Bam32/DAPP1, TAPP1/2, Lamellipodin, Btk and Akt.
We are utilize several approaches to define the function of signal transduction molecules and their interactions with one another, including sophisticated microscopic analyses of molecular processes in live cells which allow direct visualization of pathway activation and resulting protein movements. We also use genetic gain- and loss-of-function studies in mice and cultured cells and proteomic analyses to define the structure and functional significance of signal transduction complexes. Finally we study how dysregulated signaling in autoimmunity and B cell malignancies alters B cell function, with a focus on B cell:T cell interactions. Current work involves multiple human cohort studies, including team projects with the Manitoba chronic lymphocytic leukemia research cluster.
In addition to full laboratory capabilities for molecular and cell biology studies, our lab has particular expertise and capabilities in fluorescence-based cellular analyses. We currently manage a live-cell imaging confocal microscopy facility, with confocal spinning disk, FRAP and TIRF capabilities, and serve as director of the Faculty’s flow cytometry core which includes multiple FACS analyzers and a 14 parameter cell sorter.
Canadian Institutes for Health Research (2019-24) – Control of B cell metabolism by the PI3K pathway -applications for autoimmunity
Leukemia and Lymphoma Society (2017-19) - Role of follicular helper T cell populations in chronic lymphocytic leukemia
Research Manitoba (2015-20) - An Innovative Cancer Research Model: Integrated Multidisciplinary CLL Research Cluster
Canada Research Chair Tier 2 (2011-2016) - Canada Research Chair in Molecular Immunology
Ahmed Ali, Xun Wu, Nour Eissa, Jean-Eric Ghia, Francis Lin, Versha Banerjee, James Johnston, Spencer Gibson, Aaron Marshall. Distinct roles for PI3Kand PI3Kin malignant B cell migration. Nature Leukemia, 32:1958-1969.
Jayachandran, N., Hou, S., Mejia, EM, Sheikholeslami, K., Hatch, GM and Marshall, AJ. Control of B cell glycolysis via the PI3K/Akt pathway: modulation by TAPP adaptors. J. Immunol., 201:406-416.
Ahmed Y. Ali, Qingdong Guan, Xun Wu, Sen Hou, Versha Banerji, James B. Johnston, Donna Wall, David Szwajcer, Spencer B. Gibson and Aaron J. Marshall. Expression and function of PI 3-kinase delta in mesenchymal stromal cells from normal and leukemic bone marrow. British J Haematology, 185:833-887.
Jayachandran, N., Landego, I, Hou, S, Alessi, DR and Marshall, AJ. B-cell-intrinsic function of TAPP adaptors in controlling germinal center responses and autoantibody production in mice. Eur. J. Immunol. 47:280.
Pauls, SD, Ray, A, Hou, S, Vaughan, AT, Cragg, MS, Marshall, AJ. Dynamic membrane localization of the inhibitory phosphatase SHIP: control by the BCR and FcγRIIB. J. Immunol., 97(5): 1587-96.
Li, H, Wu, X, Hou, S, Malek, M., Kielkowska, A. Noh, E, Makondo, KJ, Du, Q, Wilkins, JA, Johnston, JB, Gibson, SB, Lin, F and Marshall, AJ. Phosphatidylinositol-3,4-biphosphate and its binding protein lamellipodin regulate chemotaxis of malignant B lymphocytes. J. Immunol. 196:586.
Lafarge ST, Li H, Pauls SD, Hou S, Johnston JB, Gibson SB, Marshall AJ. ZAP-70 expression directly promotes chronic lymphocytic leukemia cell adhesion to bone marrow stromal cells. Br J Haematol. 168:139.
Hou S, Landego I, Jayachandran N, Miller A, Gibson IW, Ambrose C, Marshall AJ. Follicular dendritic cell secreted protein FDC-SP controls IgA production. Mucosal Immunol. 7:948.
Li H, Hou S, Wu X, Nandagopal S, Lin F, Kung S, Marshall AJ. The tandem PH domain-containing protein 2 (TAPP2) regulates chemokine-induced cytoskeletal reorganization and malignant B cell migration. PLoS One. 2013;8(2):e57809.
Landego I, Jayachandran N, Wullschleger S, Zhang TT, Gibson IW, Miller A, Alessi DR, Marshall AJ. Interaction of TAPP adapter proteins with phosphatidylinositol (3,4)-bisphosphate regulates B-cell activation and autoantibody production. Eur J Immunol. 42:2760. Zhang TT, Makondo KJ, Marshall AJ. p110delta phosphoinositide 3-kinase represses IgE switch by potentiating BCL6 expression. J Immunol. 188(8):3700-8.
Jennifer Costantini, Samuel M.S. Cheung, Sen Hou, Hongzhao Li, Sam Kung, John Wilkins and Aaron J. Marshall. TAPP2 links phosphoinositide 3-kinase signaling to B cell adhesion through interaction with the cytoskeletal protein utrophin: expression of a novel cell adhesion-promoting complex in B cell leukemia. Blood Journal, 114:4703-12.
Ting-ting Zhang, Klaus Okkenhaug, Kamal Puri, Zachary Knight, Kevan Shokat, Bart Vanhaesebroeck and Aaron J. Marshall. Phosphoinositide 3-kinase signaling antagonizes IgE production. J. Allergy Clin. Immunol., 122:811.
Monther M. Al-Alwan, Sen Hou, Klaus Okkenhaug, Bart Vanhaesebroeck, Joel S. Hayflick and Aaron J. Marshall. Requirement for phosphoinositide 3-kinase p110delta signaling in B cell antigen receptor-mediated antigen presentation. J. Immunol. 178:2328-35.
Allam, A., Niiro, H., Clark, E.A. and A.J. Marshall. The adaptor protein Bam32 regulates Rac1 activation and actin remodeling through a phosphorylation-dependent mechanism. J. Biol. Chem., 279:39775.
Marshall, A.J., A.K. Krahn, K. Ma, V. Duronio and S. Hou. TAPP1 and TAPP2 are novel targets of phosphatidylinositol 3-kinase signaling: Sustained plasma membrane recruitment triggered by the B cell antigen receptor. Mol. Cell. Biol. 22: 5479-91.
Marshall, A.J., H. Niiro, C.G. Lerner, T.Y. Yun, S. Thomas, C.M. Disteche, and E.A. Clark. A novel B lymphocyte-associated adaptor protein, Bam32, regulates antigen receptor signaling downstream of phosphatidylinositol 3-kinase. J. Exp. Med. 191:1319.