An Elmo–Dock complex locally controls Rho GTPases and actin remodeling during cadherin-mediated adhesion

Toret, Christopher P.; Collins, Caitlin; Nelson, W. James

doi:10.1083/jcb.201406135

Cited by 42 publications

(51 citation statements)

References 37 publications

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“…Elmo proteins act as scaffolding proteins that bind to DOCK proteins, which are Rac guanine exchange factors (GEFs). These authors showed that a DOCK-Elmo complex (consisting of DOCK1 and Elmo2) transiently localizes to nascent cell-cell contacts in Madin-Darby canine kidney cells, where it colocalizes with areas of Rac activity and results in the recruitment of E-cadherin and the local reorganization of actin (Toret et al, 2014). Although DOCKElmo complexes have established roles in regulating focal adhesion dynamics during cell migration and spreading on ECM, the biological roles of these proteins can now be expanded beyond focal adhesions to include important effects in the maturation of adherens junctions.…”

Section: Micropatterningmentioning

confidence: 99%

“…A recent study by Nelson and colleagues demonstrates that the activation of Rac at adherens junctions is under the control of Elmo and DOCK proteins (Toret et al, 2014). Elmo proteins act as scaffolding proteins that bind to DOCK proteins, which are Rac guanine exchange factors (GEFs).…”

Section: Micropatterningmentioning

confidence: 99%

“…However, we speculate that these sitespecific phosphorylations of vinculin at adherens junctions and focal adhesions might also allow for the site-specific recruitment of distinct SH2-containing proteins, which could then initiate spatially distinct signaling pathways. Indeed, the recruitment of distinct DOCK-ELMO complexes to focal adhesions and adherens junctions (Toret et al, 2014) provides a conceptual framework for understanding how cadherins and integrins might spatially or kinetically direct Rac activity.…”

Section: Regulation Of Mechanosignaling and Forces By Crosstalk Betwementioning

confidence: 99%

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The mechanical regulation of integrin–cadherin crosstalk organizes cells, signaling and forces

Mui

Chen

Assoian

2016

Journal of Cell Science

230

206

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Cadherins and integrins are intrinsically linked through the actin cytoskeleton and share common signaling molecules. Although mechanosensing by the integrin-actin axis has long been appreciated, a growing body of literature now demonstrates that cadherins also transduce and respond to mechanical forces. Mounting evidence shows that mechanically driven crosstalk between integrins and cadherins regulates the spatial distribution of these receptors, their signaling intermediates, the actin cytoskeleton and intracellular forces. This interplay between integrins and cadherins can control fibronectin matrix assembly and signaling, and a fine balance between traction forces at focal adhesions and intercellular tension at adherens junctions is crucial for directional collective cell migration. In this Commentary, we discuss two central ideas: (1) how the dynamic interplay between integrins and cadherins regulates the spatial organization of intracellular signals and the extracellular matrix, and (2) the emerging consensus that intracellular force is a central mechanism that dictates cell behavior, guides tissue development and ultimately drives physiology.

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Section: Micropatterningmentioning

confidence: 99%

Section: Micropatterningmentioning

confidence: 99%

Section: Regulation Of Mechanosignaling and Forces By Crosstalk Betwementioning

confidence: 99%

See 1 more Smart Citation

The mechanical regulation of integrin–cadherin crosstalk organizes cells, signaling and forces

Mui

Chen

Assoian

2016

Journal of Cell Science

230

206

View full text Add to dashboard Cite

show abstract

“…(MDCKs) (Yamada and Nelson, 2007;Toret et al, 2014), in carcinoma cells (Hidalgo-Carcedo et al, 2011) and in zebrafish gastrula cell pairs brought into contact through micropipette manipulation (Maître et al, 2012). In Xenopus gastrula cells, the intensity of staining of the fluorescently labeled F-actin cortex diminishes within minutes of contact during re-aggregation (David et al, 2014).…”

Section: Molecular Binding Energies and Cell Adhesionmentioning

confidence: 99%

“…Finally, in aggregating MDCK cells, the scaffold protein Elmo2 transiently recruits the Rac guanine nucleotide exchange factor (GEF) Dock1 to nascent cellcell contacts. Dock1 activates the small GTPase Rac, which in turn attenuates RhoA activity at adhesion sites and promotes the dissolution of the actomyosin cortex (Toret et al, 2014).…”

Section: Molecular Binding Energies and Cell Adhesionmentioning

confidence: 99%

Cell adhesion strength from cortical tension – an integration of concepts

Winklbauer

2015

Journal of Cell Science

154

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Morphogenetic mechanisms such as cell movement or tissue separation depend on cell attachment and detachment processes, which involve adhesion receptors as well as the cortical cytoskeleton. The interplay between the two components is of stunning complexity. Most strikingly, the binding energy of adhesion molecules is usually too small for substantial cell-cell attachment, pointing to a main deficit in our present understanding of adhesion. In this Opinion article, I integrate recent findings and conceptual advances in the field into a coherent framework for cell adhesion. I argue that active cortical tension is best viewed as an integral part of adhesion, and propose on this basis a non-arbitrary measure of adhesion strength -the tissue surface tension of cell aggregates. This concept of adhesion integrates heterogeneous molecular inputs into a single mechanical property and simplifies the analysis of attachment-detachment processes. It draws attention to the enormous variation of adhesion strengths among tissues, whose origin and function is little understood.

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Biallelic loss‐of‐function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth

et al. 2020

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The family of Tre2‐Bub2‐Cdc16 (TBC)‐domain containing GTPase activating proteins (RABGAPs) is not only known as key regulatorof RAB GTPase activity but also has GAP‐independent functions. Rab GTPases are implicated in membrane trafficking pathways, such as vesicular trafficking. We report biallelic loss‐of‐function variants in TBC1D2B, encoding a member of the TBC/RABGAP family with yet unknown function, as the underlying cause of cognitive impairment, seizures, and/or gingival overgrowth in three individuals from unrelated families. TBC1D2B messenger RNA amount was drastically reduced, and the protein was absent in fibroblasts of two patients. In immunofluorescence analysis, ectopically expressed TBC1D2B colocalized with vesicles positive for RAB5, a small GTPase orchestrating early endocytic vesicle trafficking. In two independent TBC1D2B CRISPR/Cas9 knockout HeLa cell lines that serve as cellular model of TBC1D2B deficiency, epidermal growth factor internalization was significantly reduced compared with the parental HeLa cell line suggesting a role of TBC1D2B in early endocytosis. Serum deprivation of TBC1D2B‐deficient HeLa cell lines caused a decrease in cell viability and an increase in apoptosis. Our data reveal that loss of TBC1D2B causes a neurodevelopmental disorder with gingival overgrowth, possibly by deficits in vesicle trafficking and/or cell survival.

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An Elmo–Dock complex locally controls Rho GTPases and actin remodeling during cadherin-mediated adhesion

Abstract: Elmo–Dock complexes are involved not just in integrin-based adhesions but also in the initial formation of strong cadherin-based adhesions through the regulation of local Rho GTPase activity and actin remodeling.

Cited by 42 publications

References 37 publications

The mechanical regulation of integrin–cadherin crosstalk organizes cells, signaling and forces

The mechanical regulation of integrin–cadherin crosstalk organizes cells, signaling and forces

Cell adhesion strength from cortical tension – an integration of concepts

Biallelic loss‐of‐function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth

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