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A more recent version of this article appeared on June 1, 2003
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Submitted on September 26, 2002
Revised on February 14, 2003
Accepted on February 18, 2003
L/
2 integrin in Rap1-induced adhesion and migration
1 Bayer-chair Department of Molecular Immunology and Allergy, Graduate School of Medicine, Kyoto University
2 Scientific Institute San-Raffaele-DIBIT and Human Immunology Unit, University of Milano School of Medicine
3 The Center for Blood Research and Harvard Medical School Department of Pathology, Boston
* Corresponding author. E-mail address: tkinashi{at}mfour.med.kyoto-u.ac.jp.
Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity. In this study, we have defined the cytoplasmic region of the 
L and 
2 integrin that are required for Rap1-stimulated adhesion and subsequent migration on ICAM-1. Human LFA-1 bearing truncated and point-mutated L and 2 cytoplasmic regions were reconstituted in mouse IL-3-dependent proB cells, BAF/3. Truncation of the L, but not 2 subunit cytoplasmic region, abolished Rap1V12-dependent adhesion to ICAM-1. The alanine substitution of two lysine residues (K1097/K1099) in the L subunit was found to be critical in adhesion induced by Rap1V12, but not PMA. This mutation suppressed Rap1V12-induced LFA-1 conformation changes and ligand-binding affinity. The K1097/K1099 mutation also impaired binding to ICAM-1 induced by TCR crosslinking or SDF-1. In contrast, the alanine substitution for tyrosine in the 2 subunit endocytosis motif inhibited internalization of LFA-1, and severely impaired detachment at the cell rear, which resulted in long-elongated cell shapes. This result demonstrates that internalization of LFA-1 is a critical step in the de-adhesion process. Our study revealed novel requirements of amino acid residues of the LFA-1 cytoplasmic region in the response to the inside-out signaling and the subsequent de-adhesion process.
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