E-cadherin Homophilic Ligation Directly Signals through Rac and Phosphatidylinositol 3-Kinase to Regulate Adhesive Contacts (original) (raw)
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Cadherins and tissue formation: integrating adhesion and signaling
BioEssays, 1999
Cadherins and other cell-substrate and cell-cell adhesion molecules play an essential role during development. Through their cytoplasmic interaction with the cytoskeleton, cell adhesion molecules physically link cells with the extracellular matrix and/or with each other. These interactions create architectural and structural entities that enable the tissues in the embryo to restrain the physical forces encountered during development. Regulated cell adhesion is also often the driving force of morphogenetic movements. This review goes beyond the adhesive aspect of cadherins, focusing on their roles as signaling molecules in development. We discuss how cadherins, through their effects on cell proliferation, cell death, cell polarization, and differentiation, play a role in the formation of tissues and organs in the developing embryo.
Immediate-Early Signaling Induced by E-cadherin Engagement and Adhesion
Journal of Biological Chemistry, 2008
Epithelial cell-cell interactions require localized adhesive interactions between E-cadherin on opposing membranes and the activation of downstream signaling pathways that affect membrane and actin dynamics. However, it is not known whether E-cadherin engagement and activation of these signaling pathways are locally coordinated or whether signaling is sustained or locally down-regulated like other receptor-mediated pathways. To obtain high spatiotemporal resolution of immediate-early signaling events upon E-cadherin engagement, we used laser tweezers to place beads coated with functional E-cadherin extracellular domain on cells. We show that cellular E-cadherin accumulated rapidly around beads, reaching a sustained plateau level in 1-3 min. Phosphoinositides and Rac1 co-accumulated with E-cadherin, reached peak levels with E-cadherin, but then rapidly dispersed. Both E-cadherin and Rac1 accumulated independently of Rac1 GTP binding/hydrolysis, but these activities were required for Rac1 dispersal. E-cadherin accumulation was dependent on membrane dynamics and actin polymerization, but actin did not stably co-accumulate with E-cadherin; mathematical modeling showed that diffusionmediated trapping could account for the initial E-cadherin accumulation. We propose that initial E-cadherin accumulation requires active membrane dynamics and involves diffusion-mediated trapping at contact sites; to propagate further contacts, phosphatidylinositol 3-kinase and Rac1 are transiently activated by E-cadherin engagement and initiate a new round of membrane dynamics, but they are subsequently suppressed at that site to allow maintenance of weak E-cadherin mediated adhesion.
The Journal of cell biology, 1996
Epithelial cell-cell adhesion requires interactions between opposing extracellular domains of E-cadherin, and among the cytoplasmic domain of E-cadherin, catenins, and actin cytoskeleton. Little is known about how the cadherin-catenin-actin complex is assembled upon cell-cell contact, or how these complexes initiate and strengthen adhesion. We have used time-lapse differential interference contrast (DIC) imaging to observe the development of cell-cell contacts, and quantitative retrospective immunocytochemistry to measure recruitment of proteins to those contacts. We show that E-cadherin, alpha-catenin, and beta-catenin, but not plakoglobin, coassemble into Triton X-100 insoluble (TX-insoluble) structures at cell-cell contacts with kinetics similar to those for strengthening of E-cadherin-mediated cell adhesion (Angres, B., A. Barth, and W.J. Nelson. 1996. J. Cell Biol. 134:549-557). TX-insoluble E-cadherin, alpha-catenin, and beta-catenin colocalize along cell-cell contacts in spat...
The Journal of cell biology, 1993
Cell-cell adhesion is at the top of a molecular cascade of protein interactions that leads to the remodeling of epithelial cell structure and function. The earliest events that initiate this cascade are poorly understood. Using high resolution differential interference contrast microscopy and retrospective immunohistochemistry, we observed that cell-cell contact in MDCK epithelial cells consists of distinct stages that correlate with specific changes in the interaction of E-cadherin with the cytoskeleton. We show that formation of a stable contact is preceded by numerous, transient contacts. During this time and immediately following formation of a stable contact, there are no detectable changes in the distribution, relative amount, or Triton X-100 insolubility of E-cadherin at the contact. After a lag period of approximately 10 min, there is a rapid acquisition of Triton X-100 insolubility of E-cadherin localized to the stable contact. Significantly, the total amount of E-cadherin ...
Making and breaking contacts: the cellular biology of cadherin regulation
Current Opinion in Cell Biology, 2007
Cadherin-mediated cell-cell interactions are dynamic processes and cadherin function is tightly regulated in response to cellular context and signaling. Ultimately, cadherin regulation is likely to reflect the interplay between a range of fundamental cellular processes, including surface organization of receptors, cytoskeletal organization and cell trafficking, that are coordinated by signaling events. In this review we focus on recent advances in understanding how interplay with membrane trafficking and other cell-cell junctions can control cadherin function. The endocytosis of cadherins, and their post-internalization fate, influence surface expression and metabolic stability of these adhesion receptors. Similarly, at the surface, components of tight junctions provide a mode of cross-talk that regulates assembly of adherens junctions.
Cadherin-mediated cell–cell adhesion: sticking together as a family
Current Opinion in Structural Biology, 2003
The cadherins comprise a family of single-pass transmembrane proteins critical for cell-cell adhesion in vertebrates and invertebrates. The recently determined structure of the whole ectodomain from C-cadherin suggests that the adhesion of cadherins presented by juxtaposed cells is mediated by a strand-swapped dimer in which core hydrophobic elements are exchanged between the partner molecules. Sequence analysis suggests that several cadherin subfamilies share this adhesive mechanism. Recent work has shed new light on the molecular basis of cadherin adhesion, although understanding the specificity of these interactions remains a major challenge.
Journal of Biological Chemistry, 2003
Classic cadherins are adhesion-activated cell signaling receptors. In particular, homophilic cadherin ligation can directly activate Rho family GTPases and phosphatidylinositol 3-kinase (PI3-kinase), signaling molecules with the capacity to support the morphogenetic effects of these adhesion molecules during development and disease. However, the molecular basis for cadherin signaling has not been elucidated, nor is its precise contribution to cadherin function yet understood. One attractive hypothesis is that cadherin-activated signaling participates in stabilizing adhesive contacts (Yap, A. S., and Kovacs, E. M. (2003) J. Cell Biol. 160, 11-16). We now report that minimal mutation of the cadherin cytoplasmic tail to uncouple binding of p120ctn ablated the ability of E-cadherin to activate Rac. This was accompanied by profound defects in the capacity of cells to establish stable adhesive contacts, defects that were rescued by sustained Rac signaling. These data provide direct evidence for a role of cadherin-activated Rac signaling in contact formation and adhesive stabilization. In contrast, cadherin-activated PI3-kinase signaling was not affected by loss of p120-ctn binding. The molecular requirements for E-cadherin to activate Rac signaling thus appear distinct from those that stimulate PI3-kinase, and we postulate that p120-ctn may play a central role in the E-cadherin-Rac signaling pathway.
Inside-out regulation of E-cadherin conformation and adhesion
ABSTRACTCadherin cell-cell adhesion proteins play key roles in tissue morphogenesis and wound healing. Cadherin ectodomains bind in two conformations, X-dimers and strand-swap dimers, with different adhesive properties. However, the mechanisms by which cells regulate ectodomain conformation are unknown. Cadherin intracellular regions associate with several actin-binding proteins including vinculin, which are believed to tune cell-cell adhesion, solely by remodeling the actin cytoskeleton. Here, we demonstrate that vinculin association with the cadherin cytoplasmic region, also allosterically regulates ectodomain structure and adhesion, by converting weaker X-dimers into stronger strand-swap dimers. We also show that in epithelial cells, only half of apical cadherins are linked to the cytoskeleton. Furthermore, only 70% of apical cadherins form strand-swap dimers while the remaining form X-dimers, which provides cells with two cadherin pools with different adhesive properties. Our re...
E-Cadherin Adhesion Activates c-Src Signaling at Cell-Cell Contacts
Molecular Biology of the Cell, 2007
Cadherin-based cell–cell contacts are prominent sites for phosphotyrosine signaling, being enriched in tyrosine-phosphorylated proteins and tyrosine kinases and phosphatases. The functional interplay between cadherin adhesion and tyrosine kinase signaling, however, is complex and incompletely understood. In this report we tested the hypothesis that cadherin adhesion activates c-Src signaling and sought to assess its impact on cadherin function. We identified c-Src as part of a cadherin-activated cell signaling pathway that is stimulated by ligation of the adhesion receptor. However, c-Src has a biphasic impact on cadherin function, exerting a positive supportive role at lower signal strengths, but inhibiting function at high signal strengths. Inhibiting c-Src under circumstances when it is activated by cadherin adhesion decreased several measures of cadherin function. This suggests that the cadherin-activated c-Src signaling pathway serves positively to support cadherin function. Fi...