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Vol. 14, Issue 6, 2570-2582, June 2003
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L/
2 Integrin in Rap1-induced Adhesion and Migration
* Bayer-chair department of Molecular Immunology and Allergy, Graduate School of
Medicine, Kyoto University, Kyoto 606-8501, Japan;
Scientific Institute San-Raffaele-DIBIT and Human Immunology Unit, University
of Milano School of Medicine, Milan, I-20132 Italy; and
The Center for Blood Research and Harvard Medical School Department of
Pathology, Boston, Massachusetts 02115
Submitted September 26, 2002;
Revised February 14, 2003;
Accepted February 26, 2003
Monitoring Editor: Mark H. Ginsberg
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 cross-linking 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 deadhesion 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 deadhesion process.
Online version of this article contains video material. Online verision is
available at
www.molbiolcell.org.
Corresponding author. E-mail address:
tkinashi{at}mfour.med.kyoto-u.ac.jp.
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