Identification of Inhibitors of Integrin Cytoplasmic Domain Interactions With Syk.

Frontiers in immunology 2020

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Leukocyte inflammatory responses require integrin cell-adhesion molecule signaling through spleen tyrosine kinase (Syk), a non-receptor kinase that binds directly to integrin β-chain cytoplasmic domains. Here, we developed a high-throughput screen to identify small molecule inhibitors of the Syk-integrin cytoplasmic domain interactions. Screening small molecule compound libraries identified the β-lactam antibiotics cefsulodin and ceftazidime, which inhibited integrin β-subunit cytoplasmic domain binding to the tandem SH2 domains of Syk (IC50 range, 1.02-4.9 µM). Modeling suggested antagonist binding to Syk outside the pITAM binding site. Ceftazidime inhibited integrin signaling via Syk, including inhibition of adhesion-dependent upregulation of interleukin-1β and monocyte chemoattractant protein-1, but did not inhibit ITAM-dependent phosphorylation of Syk mediated by FcγRI signaling. Our results demonstrate a novel means to target Syk independent of its kinase and pITAM binding sites such that integrin signaling via this kinase is abrogated but ITAM-dependent signaling remains intact. As integrin signaling through Syk is essential for leukocyte activation, this may represent a novel approach to target inflammation. Copyright © 2021 Bakthavatsalam, Craft, Kazansky, Nguyen, Bae, Caivano, Gundlach, Aslam, Ali, Gupta, Lin, Parthiban, Vanderslice, Stephan and Woodside.

Citation

Deenadayalan Bakthavatsalam, John W Craft, Anna Kazansky, Nghi Nguyen, Goeun Bae, Amy R Caivano, C William Gundlach, Asra Aslam, Safa Ali, Shashikant Gupta, Sophie Y Lin, Hema D Parthiban, Peter Vanderslice, Clifford C Stephan, Darren G Woodside. Identification of Inhibitors of Integrin Cytoplasmic Domain Interactions With Syk. Frontiers in immunology. 2020;11:575085