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Differential Requirements for LFA-1 Binding to ICAM-1 and LFA-1-Mediated Cell Aggregation¹

Harvard Medical School, Center for Blood Research, Boston, MA 02115

Cellular adhesion through the ß₂ integrin lymphocyte function-associated Ag (LFA)-1 is a complex event involving activation, ligand binding, and cell shape changes that ultimately result in enhanced adhesion. In this report we define requirements for ligand binding and post receptor signaling by comparing two mechanisms of activation of LFA-1: 1) inside-out signaling and 2) direct activation by the ß₂ Ab, CBR LFA-1/2. Our results demonstrate that activation of LFA-1 binding to ICAM-1 by CBR LFA-1/2, in contrast to inside-out signaling mechanisms, does not require protein kinase C activation or protein phosphatase 2A activity nor is it affected by agents that interfere with reorganization of the cytoskeleton. Inhibition of protein tyrosine kinase activity does not affect ICAM-1 binding by either mechanism of activation. However, activation by either mode does require the presence of the ß cytoplasmic domain; deletion of the C-terminal phenylalanine or the five amino acid stretch between 756–762 abolished activation of LFA-1. This, combined with the observation that intracellular energy pools must be preserved, implicates the ß cytoplasmic domain in a key energy-dependent conformational change in LFA-1 that is required to achieve enhanced ligand binding. Post ligand binding events induced by both PMA and Ab stimulation, as measured by homotypic aggregation, require protein tyrosine kinase, phosphatase, and RhoA activities. By examining both ligand binding and aggregation, we have been able to dissect the signaling components critical in the multistep process of LFA-1-mediated cellular adhesion.

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