title: Phosphorylation of Rab5a protein by protein kinase Cϵ is crucial for T-cell migration.
abstract: Rab GTPases control membrane traffic and receptor-mediated endocytosis. Within this context, Rab5a plays an important role in the spatial regulation of intracellular transport and signal transduction processes. Here, we report a previously uncharacterized role for Rab5a in the regulation of T-cell motility. We show that Rab5a physically associates with protein kinase Cϵ (PKCϵ) in migrating T-cells. After stimulation of T-cells through the integrin LFA-1 or the chemokine receptor CXCR4, Rab5a is phosphorylated on an N-terminal Thr-7 site by PKCϵ. Both Rab5a and PKCϵ dynamically interact at the centrosomal region of migrating cells, and PKCϵ-mediated phosphorylation on Thr-7 regulates Rab5a trafficking to the cell leading edge. Furthermore, we demonstrate that Rab5a Thr-7 phosphorylation is functionally necessary for Rac1 activation, actin rearrangement, and T-cell motility. We present a novel mechanism by which a PKCϵ-Rab5a-Rac1 axis regulates cytoskeleton remodeling and T-cell migration, both of which are central for the adaptive immune response.
authors.affiliation: From the From the Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland.
authors.forename: Seow Theng
authors.initials: ST
authors.lastname: Ong
authors.affiliation: From the From the Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Freeley
authors.affiliation: From the From the Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland, Department of Applied Pharmacy and Bioengineering, Medical University of Warsaw, 02-091 Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Skubis-Zegadło
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637553.
authors.forename: Mobashar Hussain Urf Turabe
authors.initials: MH
authors.lastname: Fazil
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637553, Faculty of Medicine, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom, and.
authors.forename: Dermot
authors.initials: D
authors.lastname: Kelleher
authors.affiliation: the Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, A-6020 Innsbruck, Austria.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Fresser
authors.affiliation: the Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, A-6020 Innsbruck, Austria.
authors.forename: Gottfried
authors.initials: G
authors.lastname: Baier
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637553, nkverma@ntu.edu.sg.
authors.forename: Navin Kumar
authors.initials: NK
authors.lastname: Verma
authors.affiliation: From the From the Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland, longai@tcd.ie.
authors.forename: Aideen
authors.initials: A
authors.lastname: Long
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D010766:Phosphorylation / Q000502:physiology; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C527276:CXCR4 protein, human; D016169:Lymphocyte Function-Associated Antigen-1; D019718:Receptors, CXCR4; C497255:PRKCE protein, human; D051744:Protein Kinase C-epsilon; D020696:rab5 GTP-Binding Proteins
keywords: Cell Migration; Cell Signaling; Immunology; Integrin; Phosphorylation; Rab Proteins; Signal Transduction; T-cell