Spatially restricted activation of RhoA signalling at epithelial junctions by p114RhoGEF drives junction formation and morphogenesis

Terry, Stephen J.; Zihni, Ceniz; Elbediwy, Ahmed; Vitiello, Elisa; San, Isabelle V. Leefa Chong; Balda, María S.; Matter, Karl

doi:10.1038/ncb2156

Cited by 215 publications

(325 citation statements)

References 39 publications

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“…Although ARHGEF18 was previously implicated in controlling cell migration, our data now indicate that the RhoGEF ARHGEF18 acts downstream of EPB41L5-regulated cellular spreading in the cell-specific context of podocytes (Fig. 6) (39). In agreement with the known role of ARHGEF18 as a RHOGEF activator for RhoA, we observed decreased levels of active RhoA and concomitantly increased activation of Rac1 in EPB41L5 knockout cells during spreading (Fig.…”

Section: Discussionsupporting

confidence: 77%

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

Schell

Rogg

Suhm

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Podocytes form the outer part of the glomerular filter, where they have to withstand enormous transcapillary filtration forces driving glomerular filtration. Detachment of podocytes from the glomerular basement membrane precedes most glomerular diseases. However, little is known about the regulation of podocyte adhesion in vivo. Thus, we systematically screened for podocyte-specific focal adhesome (FA) components, using genetic reporter models in combination with iTRAQ-based mass spectrometry. This approach led to the identification of FERM domain protein EPB41L5 as a highly enriched podocyte-specific FA component in vivo. Genetic deletion of Epb41l5 resulted in severe proteinuria, detachment of podocytes, and development of focal segmental glomerulosclerosis. Remarkably, by binding and recruiting the RhoGEF ARGHEF18 to the leading edge, EPB41L5 directly controls actomyosin contractility and subsequent maturation of focal adhesions, cell spreading, and migration. Furthermore, EPB41L5 controls matrixdependent outside-in signaling by regulating the focal adhesome composition. Thus, by linking extracellular matrix sensing and signaling, focal adhesion maturation, and actomyosin activation EPB41L5 ensures the mechanical stability required for podocytes at the kidney filtration barrier. Finally, a diminution of EPB41L5-dependent signaling programs appears to be a common theme of podocyte disease, and therefore offers unexpected interventional therapeutic strategies to prevent podocyte loss and kidney disease progression.focal adhesion | actomyosin | podocyte | FSGS

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Section: Discussionsupporting

confidence: 77%

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

Schell

Rogg

Suhm

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Several junction-associated proteins are implicated, directly or indirectly, in the control of the activity of Rho family GTPases in epithelia (8, 16 -23). Among these, cingulin and paracingulin (also known as cingulin-like protein 1, CGNL1, or JACOP) (24 -27) play an important role in the regulation of RhoA and Rac1 activities (27)(28)(29)(30). For example, both cingulin and paracingulin recruit GEF-H1, a RhoA activator, to junctions, resulting in the down-regulation of RhoA activity in confluent monolayers (28,29,31).…”

Section: Tight Junctions (Tj)mentioning

confidence: 99%

A Role for ZO-1 and PLEKHA7 in Recruiting Paracingulin to Tight and Adherens Junctions of Epithelial Cells

Pulimeno

Paschoud

Citi

2011

Journal of Biological Chemistry

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Paracingulin is a 160-kDa protein localized in the cytoplasmic region of epithelial tight and adherens junctions, where it regulates RhoA and Rac1 activities by interacting with guanine nucleotide exchange factors. Here, we investigate the molecular mechanisms that control the recruitment of paracingulin to cell-cell junctions. We show that paracingulin forms a complex with the tight junction protein ZO-1, and the globular head domain of paracingulin interacts directly with ZO-1 through an N-terminal region containing a conserved ZIM (ZO-1-Interaction-Motif) sequence. Recruitment of paracingulin to cadherinbased cell-cell junctions in Rat1 fibroblasts requires the ZIMcontaining region, whereas in epithelial cells removal of this region decreases the junctional localization of paracingulin at tight junctions but not at adherens junctions. Depletion of ZO-1, but not ZO-2, reduces paracingulin accumulation at tight junctions. A yeast two-hybrid screen identifies both ZO-1 and the adherens junction protein PLEKHA7 as paracingulin-binding proteins. Paracingulin forms a complex with PLEKHA7 and its interacting partner p120ctn, and the globular head domain of paracingulin interacts directly with a central region of PLEKHA7. Depletion of PLEKHA7 from Madin-Darby canine kidney cells results in the loss of junctional localization of paracingulin and a decrease in its expression. In summary, we characterize ZO-1 and PLEKHA7 as paracingulin-interacting proteins that are involved in its recruitment to epithelial tight and adherens junctions, respectively. Tight junctions (TJ)2 and adherens junctions (AJ) are key elements of the apical junctional complex of vertebrate epithelial cells and are of fundamental importance in the morphogenesis and homeostasis of epithelial tissues. TJ and AJ carry out several functions: canonical roles in cell-cell adhesion and tissue sorting (AJ), cell polarization and permeability barrier functions (TJ), and signaling functions through pathways that control the organization of the cytoskeleton and the activity of transcription factors (for review, see Refs.

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“…Although this fact reflects the complex context-specific modes of Rho activation, the mechanisms of GEF regulation remain poorly characterized (12). GEF-H1 (ArhGEF2, also referred to as Lfc in mice) is a GEF that has been implicated in both RhoA and Rac activation induced by various stimuli in epithelia, including renal tubular cells (13,14). It was initially described as an exchange factor for RhoA and Rac, although its role as a Rho exchange factor is much better characterized (15) (reviewed in Ref.…”

mentioning

confidence: 99%

Role of Guanine Nucleotide Exchange Factor-H1 in Complement-mediated RhoA Activation in Glomerular Epithelial Cells

Mouawad

Aoudjit

Jiang

et al. 2014

Journal of Biological Chemistry

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Background: Disruption of the actin cytoskeleton-dependent structural integrity of glomerular epithelial cells (GEC) leads to glomerular dysfunction. Results: We have identified molecular mechanisms through which the injury-causing complement complex induces cytoskeletal changes in GEC. Conclusion: Complement-induced activation of the ERK/GEF-H1/RhoA pathway protects GEC from cell death. Significance: This study furthers our understanding of mechanisms underlying GEC foot process effacement and functional impairment in immune mediated glomerular diseases.

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Spatially restricted activation of RhoA signalling at epithelial junctions by p114RhoGEF drives junction formation and morphogenesis

Cited by 215 publications

References 39 publications

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

A Role for ZO-1 and PLEKHA7 in Recruiting Paracingulin to Tight and Adherens Junctions of Epithelial Cells

Role of Guanine Nucleotide Exchange Factor-H1 in Complement-mediated RhoA Activation in Glomerular Epithelial Cells

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