HRV-induced Syk recruitment and activation is dependent of the SH2 domains
C. Lau, P. Castellanos, T. Mazzulli, C. W. Chow (Toronto, ON, Canada)
Source: Annual Congress 2008 - Mechanisms of respiratory infections: interaction between the pathogen and the host
Disease area: Airway diseases
Abstract HRV is the leading cause of asthma and COPD exacerbations. We identified Syk tyrosine kinase to be an important mediator of HRV signaling. Using BEAS-2B human airway epithelial cells (AEC), we showed that HRV binding to its major receptor, ICAM-1, is sufficient to induce Syk activation, leading to p38 activation and IL-8 expression (Wang X, J Immunol 2007). We also found Syk to regulate clathrin-mediated HRV endocytosis via activation of PI3K/Akt (Lau C, J Immunol 2008). The aim of this project is to identify specific regions of Syk that regulate Syk activity in the HRV-ICAM-1 signaling pathway. Syk activation in the leukocytes is dependent on its SH2 domains, which bind to the i mmuno-t yrosine a ctivation m otif (ITAM) of immunoreceptors. AEC lack immunoreceptors. However, ezrin, a cytoskeletal linker protein that is highly expressed in AEC, possesses an ITAM. We have shown it to form an ICAM-1-ezrin-Syk protein complex following HRV infection. We hypothesize that Syk-SH2 domains mediate recruitment to the membrane following HRV infection, and regulate downstream signaling to PI3K/Akt. Using GFP-tagged Syk constructs, we showed by confocal microscopy that the SykR46/201A SH2 domain mutant significantly impaired Syk recruitment to the plasma membrane following HRV inoculation, when compared with wild-type Syk. Overexpression of the kinase-inactive SykK396R mutant did not affect its recruitment suggesting that kinase activity is not required for membrane translocation. However, overexpression of SykR46/201A or SykK396R mutant abrogated Akt phosphorylation, as assessed by Western analysis, indicating that both intact SH2 domains and Syk kinase activity are required for HRV signaling.
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C. Lau, P. Castellanos, T. Mazzulli, C. W. Chow (Toronto, ON, Canada). HRV-induced Syk recruitment and activation is dependent of the SH2 domains. Eur Respir J 2008; 32: Suppl. 52, 2295
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