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J. Biol. Chem., Vol. 276, Issue 38, 35967-35977, September 21, 2001
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From the Canadian Institutes of Health Research Group in
Matrix Dynamics Faculty of Dentistry, University of Toronto,
Toronto, Ontario M5S 3E2, Canada
Cells in mechanically active environments form
extensive, cadherin-mediated intercellular junctions that are important
in tissue remodeling and differentiation. Currently, it is unknown whether adherens junctions in connective tissue fibroblasts transmit mechanical signals and coordinate multicellular adaptations to physical
forces. We hypothesized that cadherins mediate intercellular mechanotransduction by activating calcium-permeable, stretch-sensitive channels. Human gingival fibroblasts in suspension were plated on
established homotypic monolayer cultures. The cells formed intercellular adherens junctions. Controlled mechanical forces were
applied to intercellular junctions by electromagnets acting on cells
containing internalized magnetite beads. At early but not later stages
of intercellular attachment, force application visibly displaced
magnetite bead-loaded cells and induced robust Ca2+
transients (65 ± 9.4 nM above base line). Similar
Ca2+ transients were induced by force application to
anti-N-cadherin antibody-coated magnetite beads. Ca2+
responses depended on influx of extracellular Ca2+ through
mechanosensitive channels because both Ca2+ chelation and
gadolinium chloride abolished the response and MnCl2
quenched fura-2 fluorescence after force application. Force application
induced accumulation of microinjected rhodamine-actin at intercellular
contacts; actin assembly was inhibited by buffering intracellular
calcium fluxes. Our results indicate that mechanical forces applied to
adherens junctions activate stretch-sensitive calcium-permeable
channels and increase actin polymerization. We suggest that N-cadherins
in fibroblasts are intercellular mechanotransducers.
Cadherins Mediate Intercellular Mechanical Signaling in
Fibroblasts by Activation of Stretch-sensitive Calcium-permeable
Channels*
,
*
This work was supported by a Canadian Institutes of Health
Research Group Grant and Maintenance Grant as well as a Heart
and Stroke Foundation grant (to C. A. G. M.) and a CIHR
Fellowship (to K. S. K.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Rm. 244, Fitzgerald
Bldg., University of Toronto, 150 College St., Toronto, ON M5S
3E2, Canada. Tel.: 416-978-6684; Fax: 416-978-5956; E-mail: kevin_ko@hotmail.com.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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