Hepatocyte Growth Factor Acutely Perturbs Actin Filament Anchorage at the Epithelial Zonula Adherens (original) (raw)

Cadherin adhesion molecules function in close cooperation with the actin cytoskeleton. At the zonula adherens (ZA) of polarized epithelial cells, E-cadherin adhesion induces the cortical recruitment of many key cytoskeletal regulators, which act in a dynamic integrated system to regulate junctional integrity and cell-cell interactions [1-3]. This capacity for the cytoskeleton to support the ZA carries the implication that regulators of the junctional cytoskeleton might also be targeted to perturb junctional integrity. In this report, we now provide evidence for this hypothesis. We show that hepatocyte growth factor (HGF), which is well-known to disrupt cell-cell interactions, acutely perturbs ZA integrity much more rapidly than generally appreciated. This is accompanied by significant loss of junctional F-actin, a process that reflects loss of filament anchorage at the junctions. We demonstrate that this involves uncoupling of the unconventional motor myosin VI from junctional E-cadherin, a novel effect of HGF that is mediated by intracellular calcium. We conclude that regulators of the junctional cytoskeleton are likely to be major targets for cadherin junctions to be acutely modulated in development and perturbed in disease. Results and Discussion Hepatocyte growth factor (HGF) drives epithelial-to-mesenchymal transformations during development and promotes tumor invasiveness [4-8], processes distinguished by remodeling or disruption of cell-cell interactions. Similarly, after several hours of treatment with HGF, subconfluent-cultured epithelial cells separate from one another and scatter [9, 10]. This late disruptive impact on cell-cell junctions has been attributed to tyrosine phosphorylation of cadherin and/or catenin [11, 12] and increased cellular contractility [10]. We now report that HGF also very rapidly disrupts junctional integrity in established Caco-2 epithelial monolayers. Control cells displayed E-cadherin staining in a continuous apical ring, marking the zonula adherens (ZA) (Figure 1A), as well as in subapical clusters [3] (not shown). Within 15 min of HGF (5 ng/ml), however, the linear integrity of the apical ZA cadherin ring became fragmented by numerous discontinuities

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