title: HRV signaling in airway epithelial cells is regulated by ITAM-mediated recruitment and activation of Syk.
abstract: Human rhinovirus (HRV), cause of the common cold, is a leading cause of exacerbations of asthma and chronic obstruction pulmonary disease (COPD). Binding of HRV to ICAM (intercellular adhesion molecule)-1, its major receptor, induces a profound inflammatory response from airway epithelial cells. My laboratory has identified Syk tyrosine kinase to be an early regulator of HRV-ICAM-1 signalling: Syk mediates replication-independent p38 mitogen-activated protein (MAP) kinase and phosphatidyl-inositol 3 (PI3)-kinase activation, interleukin (IL)-8 expression, as well as HRV internalization via clathrin-mediated endocytosis. Syk activation is accompanied by formation of a protein complex consisting of ICAM-1, ezrin and Syk at the plasma membrane. However, the molecular mechanisms that regulate this process are not understood. In this report, we investigated the role of the Syk-SH2 domains and the ezrin ITAM (immuno-tyrosine activation motif)-like motif in HRV-induced cell activation using the human BEAS-2B airway epithelial cells. Our observations suggest that the ezrin-ITAM plays a role in Syk recruitment and activation by binding to the Syk tandem SH2 domains, as originally described in the canonical ITAM-mediating signal transduction pathway in hematopoietic cells. This report is the first to demonstrate ITAM-mediated signaling in non-hematopoietic cells, suggesting that this signaling paradigm may be more ubiquitous than previously recognized.
authors.affiliation: Division of Respirology, Multi-Organ Transplantation Programme, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Lau
authors.forename: Patricia
authors.initials: P
authors.lastname: Castellanos
authors.forename: Dimitre
authors.initials: D
authors.lastname: Ranev
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Chow
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism* / Q000821:virology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012229:Rhinovirus / Q000472:pathogenicity*; D015398:Signal Transduction; D000072377:Syk Kinase; D014162:Transfection; D018909:src Homology Domains; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D018799:Intercellular Adhesion Molecule-1; D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D000099149:Ezrin; C000606896:SYK protein, human