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Science 301 (5640): 1720-1725

Copyright © 2003 by the American Association for the Advancement of Science

Bidirectional Transmembrane Signaling by Cytoplasmic Domain Separation in Integrins

Minsoo Kim,* Christopher V. Carman,* Timothy A. Springer{dagger}

Abstract: Although critical for development, immunity, wound healing, and metastasis, integrins represent one of the few classes of plasma membrane receptors for which the basic signaling mechanism remains a mystery. We investigated cytoplasmic conformational changes in the integrin LFA-1 ({alpha}Lß2) in living cells by measuring fluorescence resonance energy transfer between cyan fluorescent protein–fused and yellow fluorescent protein–fused {alpha}L and ß2 cytoplasmic domains. In the resting state these domains were close to each other, but underwent significant spatial separation upon either intracellular activation of integrin adhesiveness (inside-out signaling) or ligand binding (outside-in signaling). Thus, bidirectional integrin signaling is accomplished by coupling extracellular conformational changes to an unclasping and separation of the {alpha} and ß cytoplasmic domains, a distinctive mechanism for transmitting information across the plasma membrane.

CBR Institute for Biomedical Research, Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

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* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: springeroffice{at}cbr.med.harvard.edu


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Intercellular Adhesion Molecule-3 Binding of Integrin {alpha}L{beta}2 Requires Both Extension and Opening of the Integrin Headpiece.
X.-Y. Tang, Y.-F. Li, and S.-M. Tan (2008)
J. Immunol. 180, 4793-4804
   Abstract »    Full Text »    PDF »
Regulation of LFA-1-dependent inflammatory cell recruitment by Cbl-b and 14-3-3 proteins.
E. Y. Choi, V. V. Orlova, S. C. Fagerholm, S. M. Nurmi, L. Zhang, C. M. Ballantyne, C. G. Gahmberg, and T. Chavakis (2008)
Blood 111, 3607-3614
   Abstract »    Full Text »    PDF »
The N-terminal Domains of Talin Cooperate with the Phosphotyrosine Binding-like Domain to Activate {beta}1 and {beta}3 Integrins.
M. Bouaouina, Y. Lad, and D. A. Calderwood (2008)
J. Biol. Chem. 283, 6118-6125
   Abstract »    Full Text »    PDF »
RhoA Is Involved in LFA-1 Extension Triggered by CXCL12 but Not in a Novel Outside-In LFA-1 Activation Facilitated by CXCL9.
R. Pasvolsky, V. Grabovsky, C. Giagulli, Z. Shulman, R. Shamri, S. W. Feigelson, C. Laudanna, and R. Alon (2008)
J. Immunol. 180, 2815-2823
   Abstract »    Full Text »    PDF »
Quantification of integrin receptor agonism by fluorescence lifetime imaging.
M. Parsons, A. J. Messent, J. D. Humphries, N. O. Deakin, and M. J. Humphries (2008)
J. Cell Sci. 121, 265-271
   Abstract »    Full Text »    PDF »
Nonmuscle myosin heavy chain IIA mediates integrin LFA-1 de-adhesion during T lymphocyte migration.
N. A. Morin, P. W. Oakes, Y.-M. Hyun, D. Lee, Y. E. Chin, M. R. King, T. A. Springer, M. Shimaoka, J. X. Tang, J. S. Reichner, et al. (2008)
J. Exp. Med. 205, 195-205
   Abstract »    Full Text »    PDF »
A Structural Hypothesis for the Transition between Bent and Extended Conformations of the Leukocyte beta2 Integrins.
M. Shi, S. Y. Foo, S.-M. Tan, E. P. Mitchell, S. K. A. Law, and J. Lescar (2007)
J. Biol. Chem. 282, 30198-30206
   Abstract »    Full Text »    PDF »

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