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(Journal of Leukocyte Biology. 2000;68:277-283.)
© 2000 by Society for Leukocyte Biology

TNF--mediated neutrophil apoptosis involves Ly-GDI, a Rho GTPase regulator

Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin, Germany

Correspondence: Ralph Kettritz, M.D., Division of Nephrology, Franz Volhard Clinic, Wiltbergstrasse 50, 13122 Berlin, Germany.

We investigated intracellular signaling events involved in fibronectin-accelerated TNF--mediated PMN apoptosis by means of 2-D gel electrophoresis and western blotting. Proteins were sequenced with electrospray ionization mass spectrometry. Apoptosis was quantitated by flow cytometry. We detected a cluster of acidic, high molecular-weight proteins that were only tyrosine phosphorylated when TNF--treated PMN interacted with fibronectin. Sequence analysis revealed that one of these proteins was Ly-GDI, a regulator of Rho GTPases. Fibronectin increased the TNF--induced Ly-GDI cleavage, yielding a 23-kD fragment. At 8 h, intact Ly-GDI was decreased to 33% on fibronectin, compared with 69% on PolyHema (P<0.05). Inhibition of tyrosine phosphorylation prevented phosphorylation of Ly-GDI, fibronectin-accelerated Ly-GDI cleavage, and fibronectin-accelerated apoptosis in TNF--treated PMN. We found that Ly-GDI cleavage was dependent on caspase-3 activation and that caspase-3 inhibition decreased apoptosis. We conclude that tyrosine phosphorylation of Ly-GDI, followed by increased caspase-3-mediated Ly-GDI cleavage, is a signaling event associated with accelerated TNF--mediated apoptosis on fibronectin.

Key Words: apoptosis • human neutrophils • matrix • Ly-GDI • caspases

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