Identification of Inhibitors of Integrin Cytoplasmic Domain Interactions With Syk.
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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.
author list (cited authors)
Bakthavatsalam, D., Craft, J. W., Kazansky, A., Nguyen, N., Bae, G., Caivano, A. R., ... Woodside, D. G
complete list of authors
Bakthavatsalam, Deenadayalan||Craft, John W||Kazansky, Anna||Nguyen, Nghi||Bae, Goeun||Caivano, Amy R||Gundlach, C William||Aslam, Asra||Ali, Safa||Gupta, Shashikant||Lin, Sophie Y||Parthiban, Hema D||Vanderslice, Peter||Stephan, Clifford C||Woodside, Darren G