HRV Signaling in Airway Epithelial Cells Is Regulated by ITAM-Mediated Recruitment and Activation of Syk

Christine      Lau; Patricia      Castellanos; Dimitre      Ranev; Xiaomin      Wang; Chung-Wai      Chow

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.

Keywords: Airway epithelium, ezrin, human rhinovirus, ITAM, SH2 domains, Syk tyrosine kinase, HRV, ICAM, ERM, PBS, FITC, GFP, TNF, IL, ELISAAirway epithelium, ezrin, human rhinovirus, ITAM, SH2 domains, Syk tyrosine kinase, HRV, ICAM, ERM, PBS, FITC, GFP, TNF, IL, ELISA