Abl tyrosine kinases regulate cell-cell adhesion through Rho GTPases.
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.
Zandy
Nicole L
NL
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Playford
Martin
M
Pendergast
Ann Marie
AM
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000201:enzymology / Q000502:physiology; D016044:Fusion Proteins, bcr-abl; D007365:Intercellular Junctions / Q000502:physiology; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl; D020741:rho GTP-Binding Proteins