The polarity protein Scribble positions DLC3 at adherens junctions to regulate Rho signaling

Hendrick, Janina; Franz‐Wachtel, Mirita; Moeller, Yvonne; Schmid, Simone; Maček, Boris

doi:10.1242/jcs.190074

Cited by 28 publications

(34 citation statements)

References 63 publications

(31 reference statements)

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“…Taking into account the enhanced adhesion and spreading of DLC3-depleted cells, it is possible that the trafficking of integrins is also regulated in a DLC3-dependent manner. In addition to the local Rho regulation at the plasma membrane, the altered membrane trafficking in cells depleted of DLC3 most likely contributes to the impairment of epithelial adherens junctions and polarized morphogenesis described previously (Holeiter et al, 2012;Hendrick et al, 2016). In future studies, it will thus be interesting to determine, through a global approach, how DLC3 modulates the spatial distribution of membrane-associated cellular proteins.…”

Section: Discussionmentioning

confidence: 93%

“…We next asked the question how DLC3 is recruited to RhoB-positive endosomes. By performing proteomic mass spectrometry analysis, we previously identified the early endosomal adaptor protein sorting nexin 27 (SNX27) as a candidate DLC3-interacting protein (Hendrick et al, 2016). Considering that DLC3 contains a PDZ ligand (PDZL) motif and SNX27 a PDZ domain, we aimed to validate the biochemical interaction of the proteins.…”

Section: Snx27 Recruits Dlc3 To Endomembranesmentioning

confidence: 99%

“…Although the DLC proteins are structurally related, our previous work has uncovered isoform-specific cellular functions for DLC3 that are associated with its distinct subcellular localization. In breast and colonic epithelial cells, DLC3 is recruited to the plasma membrane by interacting with the PDZ domain-containing scaffold protein Scribble where DLC3 is required for adherens junction stability and polarized 3D morphogenesis (Hendrick et al, 2016;Holeiter et al, 2012). Here, we investigated the role of DLC3 in breast epithelial cells that possess invasive properties.…”

Section: Introductionmentioning

confidence: 99%

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DLC3 suppresses MT1-MMP-dependent matrix degradation by controlling RhoB and actin remodeling at endosomal membranes

Noll

Benz

Frey

et al. 2019

Journal of Cell Science

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Cancer cells degrade the extracellular matrix through actin-rich protrusions termed invadopodia. The formation of functional invadopodia requires polarized membrane trafficking driven by Rho GTPase-mediated cytoskeletal remodeling. We identify the Rho GTPase-activating protein deleted in liver cancer 3 (DLC3; also known as STARD8) as an integral component of the endosomal transport and sorting machinery. We provide evidence for the direct regulation of RhoB by DLC3 at endosomal membranes to which DLC3 is recruited by interacting with the sorting nexin SNX27. In TGF-β-treated MCF10A breast epithelial cells, DLC3 knockdown enhanced metalloproteinasedependent matrix degradation, which was partially rescued by RhoB co-depletion. This was recapitulated in MDA-MB-231 breast cancer cells in which early endosomes demonstrated aberrantly enriched F-actin and accumulated the metalloproteinase MT1-MMP (also known as MMP14) upon DLC3 knockdown. Remarkably, Rab4 (herein referring to Rab4A) downregulation fully rescued the enhanced matrix degradation of TGF-β-treated MCF10A and MDA-MB-231 cells. In summary, our findings establish a novel role for DLC3 in the suppression of MT1-MMP-dependent matrix degradation by inactivating RhoB signaling at endosomal membranes. We propose that DLC3 function is required to limit endosomal actin polymerization, Rab4-dependent recycling of MT1-MMP and, consequently, matrix degradation mediated by invadopodial activity.

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Section: Discussionmentioning

confidence: 93%

Section: Snx27 Recruits Dlc3 To Endomembranesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DLC3 suppresses MT1-MMP-dependent matrix degradation by controlling RhoB and actin remodeling at endosomal membranes

Noll

Benz

Frey

et al. 2019

Journal of Cell Science

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“…Therefore, AJ formation may be involved in nonvesicular transport of cholesterol to the plasma membrane as well. Along this line, another member of the START‐domain containing protein, deleted in liver cancer 3 (DLC‐3), was reported to localize at AJ in epithelial cells …”

Section: Aj Alter the Lipid Composition Of The Plasma Membranementioning

confidence: 95%

Cell Adhesion Structures in Epithelial Cells Are Formed in Dynamic and Cooperative Ways

Shigetomi

Ikenouchi

2019

BioEssays

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There are many morphologically distinct membrane structures with different functions at the surface of epithelial cells. Among these, adherens junctions (AJ) and tight junctions (TJ) are responsible for the mechanical linkage of epithelial cells and epithelial barrier function, respectively. In the process of new cell-cell adhesion formation between two epithelial cells, such as after wounding, AJ form first and then TJ form on the apical side of AJ. This process is very complicated because AJ formation triggers drastic changes in the organization of actin cytoskeleton, the activity of Rho family of small GTPases, and the lipid composition of the plasma membrane, all of which are required for subsequent TJ formation. In this review, the authors focus on the relationship between AJ and TJ as a representative example of specialization of plasma membrane regions and introduce recent findings on how AJ formation promotes the subsequent formation of TJ. Figure 6. Addition of cholesterol restores the formation of TJ in α-catenin KO cells. Time-lapse imaging of α-catenin KO epithelial cells expressing GFP-claudin-3. Cholesterol-saturated MβCD (75 mM) was added to the medium to restore the level of cholesterol in the plasma membrane at time 0. GFP-claudin-3 gradually accumulate at the cell-cell interface and TJ is formed even in the absence of AJ. Scale bar, 20 µm. Adapted with permission. [72]

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“…The RhoGAP protein Deleted in liver cancer 3 (DLC3, STARD8) is an excellent example for such complex regulation of Rho GTPase signaling. In polarized epithelial cells, DLC3 is targeted to adherens junctions by the scaffold protein Scribble to suppress RhoA signaling [38]. By additionally recruiting the RacGEF β-Pix (ARHGEF7), Scribble contributes to the establishment of antagonizing RhoA and Rac activity gradients along the apical-basal axis of epithelial cells [39,40].…”

Section: Spatiotemporal Rho Regulation By Gefs and Gapsmentioning

confidence: 99%

Spatiotemporal Control of Intracellular Membrane Trafficking by Rho GTPases

Noll

Haußer

2019

Cells

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As membrane-associated master regulators of cytoskeletal remodeling, Rho GTPases coordinate a wide range of biological processes such as cell adhesion, motility, and polarity. In the last years, Rho GTPases have also been recognized to control intracellular membrane sorting and trafficking steps directly; however, how Rho GTPase signaling is regulated at endomembranes is still poorly understood. In this review, we will specifically address the local Rho GTPase pools coordinating intracellular membrane trafficking with a focus on the endo-and exocytic pathways. We will further highlight the spatiotemporal molecular regulation of Rho signaling at endomembrane sites through Rho regulatory proteins, the GEFs and GAPs. Finally, we will discuss the contribution of dysregulated Rho signaling emanating from endomembranes to the development and progression of cancer.an inactive GDP-bound and an active GTP-bound state. Rho GDP/GTP cycling is tightly regulated by guanine nucleotide exchange factors (GEFs) that promote the formation of the active GTP-bound form through exchanging GDP for GTP. On the contrary, GTPase-activating proteins (GAPs) catalyze the intrinsic GTPase activity and promote the formation of inactive GDP-bound Rho. This inactive state can be subsequently recognized by guanine nucleotide dissociation inhibitors (GDIs), which sequester Rho GTPases in the cytosol [5,6] (Figure 1). Whereas classical Rho GTPases are regulated by GDP/GTP cycling, atypical Rho GTPases are regulated by other mechanisms that occur in particular at the transcriptional and post-translational level [7]. In the case of atypical Rho GTPases, GTP is usually constitutively bound, either because these Rho GTPases possess high intrinsic nucleotide exchange activity or have substitutions in their GTPase domain that prevent GTP hydrolysis.

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The polarity protein Scribble positions DLC3 at adherens junctions to regulate Rho signaling

Cited by 28 publications

References 63 publications

DLC3 suppresses MT1-MMP-dependent matrix degradation by controlling RhoB and actin remodeling at endosomal membranes

DLC3 suppresses MT1-MMP-dependent matrix degradation by controlling RhoB and actin remodeling at endosomal membranes

Cell Adhesion Structures in Epithelial Cells Are Formed in Dynamic and Cooperative Ways

Spatiotemporal Control of Intracellular Membrane Trafficking by Rho GTPases

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