Protein tyrosine phosphatase activity is necessary for E‐cadherin‐activated Src signaling

McLachlan, Robert W.; Yap, Alpha S.

doi:10.1002/cm.20492

Cited by 30 publications

(32 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Enhanced β-catenin staining and a more linear localization around the cell periphery were also observed in 8CPT-cAMP injected eyes. Changes in cell shape and junctional linearity has been correlated with increased junctional integrity and function [33], [42]. A “junctional linearity index” was calculated as described in Materials and Methods, and representative example cell values are shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Rap1 GTPase Activation and Barrier Enhancement in RPE Inhibits Choroidal Neovascularization In Vivo

et al. 2013

View full text Add to dashboard Cite

Loss of barrier integrity precedes the development of pathologies such as metastasis, inflammatory disorders, and blood-retinal barrier breakdown present in neovascular age-related macular degeneration. Rap1 GTPase is involved in regulating both endothelial and epithelial cell junctions; the specific role of Rap1A vs. Rap1B isoforms is less clear. Compromise of retinal pigment epithelium barrier function is a contributing factor to the development of AMD. We utilized shRNA of Rap1 isoforms in cultured human retinal pigment epithelial cells, along with knockout mouse models to test the role of Rap1 on promoting RPE barrier properties, with emphasis on the dynamic junctional regulation that is triggered when the adhesion between cells is challenged. In vitro, Rap1A shRNA reduced steady-state barrier integrity, whereas Rap1B shRNA affected dynamic junctional responses. In a laser-induced choroidal neovascularization (CNV) model of macular degeneration, Rap1b−/− mice exhibited larger CNV volumes compared to wild-type or Rap1a−/−. In vivo, intravitreal injection of a cAMP analog (8CPT-2′-O-Me-cAMP) that is a known Rap1 activator significantly reduced laser-induced CNV volume, which correlated with the inhibition of CEC transmigration across 8CPT-2′O-Me-cAMP-treated RPE monolayers in vitro. Rap1 activation by 8CPT-2′-O-Me-cAMP treatment increased recruitment of junctional proteins and F-actin to cell-cell contacts, increasing both the linearity of junctions in vitro and in cells surrounding laser-induced lesions in vivo. We conclude that in vitro, Rap1A may be important for steady state barrier integrity, while Rap1B is involved more in dynamic junctional responses such as resistance to junctional disassembly induced by EGTA and reassembly of cell junctions following disruption. Furthermore, activation of Rap1 in vivo inhibited development of choroidal neovascular lesions in a laser-injury model. Our data suggest that targeting Rap1 isoforms in vivo with 8CPT-2′-O-Me-cAMP may be a viable pharmacological means to strengthen the RPE barrier against the pathological choroidal endothelial cell invasion that occurs in macular degeneration.

show abstract

Section: Resultsmentioning

confidence: 99%

Rap1 GTPase Activation and Barrier Enhancement in RPE Inhibits Choroidal Neovascularization In Vivo

et al. 2013

View full text Add to dashboard Cite

show abstract

“…The absence of stiffening on E-cadherin substrata was unexpected, because E-cadherin-based adhesion supports traction forces and activates GTPases, Src and PI3K signaling (Kovacs et al, 2002;le Duc et al, 2010;McLachlan and Yap, 2011;Tabdili et al, 2012a). In addition, E-cadherin receptors are mechanically coupled to actin, and could potentially transmit force through the cytoskeleton by stress focusing (Hu et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

E-cadherin-mediated force transduction signals regulate global cell mechanics

Muhamed

Sehgal

et al. 2016

Journal of Cell Science

104

View full text Add to dashboard Cite

This report elucidates an E-cadherin-based force-transduction pathway that triggers changes in cell mechanics through a mechanism requiring epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase (PI3K), and the downstream formation of new integrin adhesions. This mechanism operates in addition to local cytoskeletal remodeling triggered by conformational changes in the E-cadherin-associated protein α-catenin, at sites of mechanical perturbation. Studies using magnetic twisting cytometry (MTC), together with traction force microscopy (TFM) and confocal imaging identified force-activated E-cadherin-specific signals that integrate cadherin force transduction, integrin activation and cell contractility. EGFR is required for the downstream activation of PI3K and myosin-II-dependent cell stiffening. Our findings also demonstrated that α-catenin-dependent cytoskeletal remodeling at perturbed E-cadherin adhesions does not require cell stiffening. These results broaden the repertoire of E-cadherin-based force transduction mechanisms, and define the force-sensitive signaling network underlying the mechano-chemical integration of spatially segregated adhesion receptors.

show abstract

“…Whether other membrane proteins contribute to selective force transduction by classical cadherins remains to be determined. Possible candidates are protocadherins (Chen and Gumbiner, 2006;Deplazes et al, 2009;Taveau et al, 2008), receptor tyrosine kinases (Brady-Kalnay et al, 1995;Hellberg et al, 2002;McLachlan and Yap, 2011) or growth factor receptors (Perrais et al, 2007;Shibamoto et al, 1994;Tzima et al, 2005;Williams et al, 2001). Recent findings demonstrated a role for protocadherin-19 in the regulation of N-cadherindependent cell-cell adhesion and migration (Papusheva and Heisenberg, 2010;Taveau et al, 2008), and PAPC regulates the adhesive activity of C-cadherin during Xenopus morphogenesis (Chen and Gumbiner, 2006).…”

Section: Discussionmentioning

confidence: 99%

Cadherin-dependent mechanotransduction depends on ligand identity but not affinity

Tabdili¹,

Langer²,

Shi³

et al. 2012

Journal of Cell Science

View full text Add to dashboard Cite

SummaryThis study investigates the relationship between classical cadherin binding affinities and mechanotransduction through cadherinmediated adhesions. The mechanical properties of cadherin-dependent intercellular junctions are generally attributed to differences in the binding affinities of classical cadherin subtypes that contribute to cohesive energies between cells. However, cell mechanics and mechanotransduction may also regulate intercellular contacts. We used micropipette measurements to quantify the two-dimensional affinities of cadherins at the cell surface, and two complementary mechanical measurements to assess ligand-dependent mechanotransduction through cadherin adhesions. At the cell surface, the classical cadherins investigated in this study form both homophilic and heterophilic bonds with two-dimensional affinities that differ by less than threefold. In contrast, mechanotransduction through cadherin adhesions is strongly ligand dependent such that homophilic, but not heterophilic ligation mediates mechanotransduction, independent of the cadherin binding affinity. These findings suggest that ligand-selective mechanotransduction may supersede differences in cadherin binding affinities in regulating intercellular contacts.

show abstract

Protein tyrosine phosphatase activity is necessary for E‐cadherin‐activated Src signaling

Cited by 30 publications

References 58 publications

Rap1 GTPase Activation and Barrier Enhancement in RPE Inhibits Choroidal Neovascularization In Vivo

Rap1 GTPase Activation and Barrier Enhancement in RPE Inhibits Choroidal Neovascularization In Vivo

E-cadherin-mediated force transduction signals regulate global cell mechanics

Cadherin-dependent mechanotransduction depends on ligand identity but not affinity

Contact Info

Product

Resources

About