Abl tyrosine kinases regulate cell–cell adhesion through Rho GTPases
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Edited by Joan S. Brugge, Harvard Medical School, Boston, MA, and approved September 14, 2007 (received for review April 3, 2007)
Abstract
Adherens junctions are calcium-dependent cell–cell contacts that link neighboring cells through cadherin receptors. Coordinated regulation of the actin cytoskeleton by the Rho GTPases is required for the formation and dissolution of adherens junctions. However, the pathways that link cadherin signaling to cytoskeletal regulation remain poorly defined. Here we identify the Abl family kinases as critical mediators of cadherin-mediated adhesion. Endogenous Abl family kinases, Abl and Arg, are activated and required for Rac activation after cadherin engagement and regulate the formation and maintenance of adherens junctions in mammalian cells. Significantly, we show that Abl-dependent regulation of the Rho–ROCK–myosin signaling pathway is critical for the maintenance of adherens junctions. Inhibition of the Abl kinases in epithelial sheets results in the activation of Rho and its downstream target ROCK, leading to enhanced phosphorylation of the myosin regulatory light chain. These signaling events result in enhanced stress fiber formation and increased actomyosin contractility, thereby disrupting adherens junctions. Conversely, Arg gain of function promotes adherens junction formation through a Crk-dependent pathway in cells with weak junctions. These data identify the Abl kinases as a regulatory link between the cadherin–catenin adhesion complex and the actin cytoskeleton through regulation of Rac and Rho during adherens junction formation, and also reveal a functional link between Abl and Rho that is essential for adherens junction stability.
Footnotes
- †To whom correspondence should be addressed. E-mail: pende014{at}mc.duke.edu
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Author contributions: A.M.P. designed research; N.L.Z. and M.P. performed research; N.L.Z. and A.M.P. analyzed data; and N.L.Z. and A.M.P. wrote the paper.
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↵*Present address: National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20982.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0703077104/DC1.
- Abbreviations:
- GAP,
- GTPase-activating protein;
- GEF,
- guanine nucleotide exchange factor;
- MEF,
- mouse embryo fibroblast;
- MLC,
- myosin regulatory light chain;
- NMJ,
- neuromuscular junction.
- © 2007 by The National Academy of Sciences of the USA
