Redox Regulation of Protein Tyrosine Kinases in Lung Health and Disease
講師：
Albert van der Vliet
所属：
バーモント大学
担当：
本橋 ほづみ（所属 遺伝子発現制御分野・内線8550）
要旨：
Protein tyrosine kinases play a central role in many cell signaling pathways, and form a major target for drug development. Among these, receptor tyrosine kinases such as the epidermal growth factor (EGFR) and Src family non-receptor tyrosine kinases are widely known for their role in cancer development and progression, and are increasingly appreciated for their involvement in non-malignant diseases such as allergic asthma and fibrotic disease. Tyrosine kinase signaling is subject to redox-dependent regulation, largely through reversible inactivation of protein tyrosine phosphatases. Recent studies by us and others indicate that various NOX-family NADPH oxidases can also promote activation of EGFR and Src in association with H2O2-mediated reversible oxidation of conserved non-catalytic cysteine residues within ATP-binding domains of these kinases, as well as other cysteines. Studies with recombinant enzymes indicated that H2O2-induced activation of these kinases is primarily due to formation of sulfenic acids (-SOH), the primarily product of H2O2-mediated cysteine oxidation, and molecular dynamics (MD) simulations have revealed structural insights into the mechanisms by which cysteine sulfenylation may enhance kinase function, which are related to unique electrostatic interactions with nearby Arg residues. These redox-based mechanisms of EGFR/Src activation were found to be critical for innate responses in airway epithelial cells to injurious triggers or airborne protease allergens, related to activation of the NOX homolog DUOX1. Moreover, enhanced expression and activation of DUOX1 and EGFR/Src within the airway epithelium were found to contribute to pathophysiology of allergic airway disease. Finally, dysregulated redox modifications within Src or EGFR in lung cancers were found to be associated with altered activation and subcellular trafficking of these kinases and increased invasive properties as well as resistance to EGFR-targeted therapies. Collectively, these observations highlight the importance of reversible cysteine modification as a novel redox-dependent regulatory mode in the diverse cellular functions of these protein tyrosine kinases.
