Coping with Loss: Cell Adaptation to Cytoskeleton Disruption

McGarry, David J.; Olson, Michael F.

doi:10.1016/j.devcel.2016.09.020

Cited by 4 publications

(3 citation statements)

References 9 publications

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“…Rho GTPases are cytoskeletal regulators essential for cell morphology and motility, and guide vesicle-mediated processes including the secretory pathway and autophagy 34 . Adaptation of cells to environmental stressors is adjusted by complex signaling networks regulated by small GTPases CDC42, Rac, and Rho 35 . Two families of GEFs, MCF2 (better known as Dbl) and DOCK coordinate the spatio-temporal activation of RAC and CDC42 proteins and their signaling into the cell 36 .…”

Section: Discussionmentioning

confidence: 99%

Extra-hematopoietic immunomodulatory role of the guanine-exchange factor DOCK2

et al. 2022

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Stromal cells interact with immune cells during initiation and resolution of immune responses, though the precise underlying mechanisms remain to be resolved. Lessons learned from stromal cell-based therapies indicate that environmental signals instruct their immunomodulatory action contributing to immune response control. Here, to the best of our knowledge, we show a novel function for the guanine-exchange factor DOCK2 in regulating immunosuppressive function in three human stromal cell models and by siRNA-mediated DOCK2 knockdown. To identify immune function-related stromal cell molecular signatures, we first reprogrammed mesenchymal stem/progenitor cells (MSPCs) into induced pluripotent stem cells (iPSCs) before differentiating these iPSCs in a back-loop into MSPCs. The iPSCs and immature iPS-MSPCs lacked immunosuppressive potential. Successive maturation facilitated immunomodulation, while maintaining clonogenicity, comparable to their parental MSPCs. Sequential transcriptomics and methylomics displayed time-dependent immune-related gene expression trajectories, including DOCK2, eventually resembling parental MSPCs. Severe combined immunodeficiency (SCID) patient-derived fibroblasts harboring bi-allelic DOCK2 mutations showed significantly reduced immunomodulatory capacity compared to non-mutated fibroblasts. Conditional DOCK2 siRNA knockdown in iPS-MSPCs and fibroblasts also immediately reduced immunomodulatory capacity. Conclusively, CRISPR/Cas9-mediated DOCK2 knockout in iPS-MSPCs also resulted in significantly reduced immunomodulation, reduced CDC42 Rho family GTPase activation and blunted filopodia formation. These data identify G protein signaling as key element devising stromal cell immunomodulation.

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Section: Discussionmentioning

confidence: 99%

Extra-hematopoietic immunomodulatory role of the guanine-exchange factor DOCK2

et al. 2022

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“…In accordance with previous reports, our data showed that Dock6 could promote the motility of GC cells by activating Rac1 and Cdc42. Recently, a compensatory mechanism for Dock6 knock-down-mediated Rac1/Cdc42 activation inhibition was reported [ 45 , 46 ]. Upon the acute knock-down of Dock6 with RNAi, the activation of Rac1 and Cdc42 was decreased, and the activation of RhoA was increased; however, when Dock6 was chronically down-regulated, ISG15 expression was inhibited, and the active states of Rac1 and Cdc42 were stabilized by IQGAP1 [ 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

miR-148b-3p inhibits gastric cancer metastasis by inhibiting the Dock6/Rac1/Cdc42 axis

Jiang

Chen

et al. 2018

J Exp Clin Cancer Res

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BackgroundOur previous work showed that some Rho GTPases, including Rho, Rac1 and Cdc42, play critical roles in gastric cancer (GC); however, how they are regulated in GC remains largely unknown. In this study, we aimed to investigate the roles and molecular mechanisms of Dock6, an atypical Rho guanine nucleotide exchange factor (GEF), in GC metastasis.MethodsThe expression levels of Dock6 and miR-148b-3p in GC tissues and paired nontumor tissues were determined by immunohistochemistry (IHC) and in situ hybridization (ISH), respectively. The correlation between Dock6/miR-148b-3p expression and the overall survival of GC patients was calculated by the Kaplan-Meier method and log-rank test. The roles of Dock6 and miR-148b-3p in GC were investigated by in vitro and in vivo functional studies. Rac1 and Cdc42 activation was investigated by GST pull-down assays. The inhibition of Dock6 transcription by miR-148b-3p was determined by luciferase reporter assays.ResultsA significant increase in Dock6 expression was found in GC tissues compared with nontumor tissues, and its positive expression was associated with lymph node metastasis and a higher TNM stage. Patients with positive Dock6 expression exhibited shorter overall survival periods than patients with negative Dock6 expression. Dock6 promoted GC migration and invasion by increasing the activation of Rac1 and Cdc42. miR-148b-3p expression was negatively correlated with Dock6 expression in GC, and it decreased the motility of GC cells by inhibiting the Dock6/Rac1/Cdc42 axis.ConclusionsDock6 was over-expressed in GC tissues, and its positive expression was associated with GC metastasis and indicated poor prognosis of GC patients. Targeting of Dock6 by miR-148b-3p could activate Rac1 and Cdc42, directly affecting the motility of GC cells. Targeting the Dock6-Rac1/Cdc42 axis could serve as a new therapeutic strategy for GC treatment.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0729-z) contains supplementary material, which is available to authorized users.

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“…3, adapted from refs. 42,43). The cage like enclosure of the mitotic chromatin by the ER-associated DOCK6 may ensure maximal exposure of kinetochores to active GTP-bound CDC42.…”

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confidence: 99%

Mechanism of cell-intrinsic adaptation to Adams-Oliver Syndrome gene DOCK6 disruption highlights ubiquitin-like modifier ISG15 as a regulator of RHO GTPases

Cerikan

Schiebel

2017

Small GTPases

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DOCK6 is a RAC1/CDC42 guanine nucleotide exchange factor, however, little is known about its function and sub-cellular localization. DOCK6 regulates the balance between RAC1 and RHOA activity during cell adhesion and is important for CDC42-dependent mitotic chromosome alignment. Surprisingly, a cell intrinsic adaptation mechanism compensates for errors in these DOCK6 functions that arise as a consequence of prolonged DOCK6 depletion or complete removal in DOCK6 knockout cells. Down-regulation of the ubiquitin-like modifier ISG15 accounts for this adaptation. Strikingly, although most other DOCK family proteins are deployed on the plasma membrane, here we show that DOCK6 localizes to the endoplasmic reticulum (ER) in dependence of its DHR-1 domain. ER localization of DOCK6 opens up new insights into its functions.

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Coping with Loss: Cell Adaptation to Cytoskeleton Disruption

Cited by 4 publications

References 9 publications

Extra-hematopoietic immunomodulatory role of the guanine-exchange factor DOCK2

Extra-hematopoietic immunomodulatory role of the guanine-exchange factor DOCK2

miR-148b-3p inhibits gastric cancer metastasis by inhibiting the Dock6/Rac1/Cdc42 axis

Mechanism of cell-intrinsic adaptation to Adams-Oliver Syndrome gene DOCK6 disruption highlights ubiquitin-like modifier ISG15 as a regulator of RHO GTPases

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