Local temporal Rac1-GTP nadirs and peaks restrict cell protrusions and retractions

Hu, Jinshan; Gong, Xiaoyi; Strömblad, Staffan

doi:10.1126/sciadv.abl3667

Cited by 8 publications

(7 citation statements)

References 57 publications

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“…The 10 most enriched pathways included biological processes involved in apoptotic pathways and protein insertion into membrane, and metabolic pathways involved in cancers, as well as some also crucial to osteoclasts, such as PI3K‐Akt and mTOR. Finally, another pathway of interest was highlighted, as the most enriched pathway “Rac protein signal transduction,” as well as “Negative regulation of cell size,” which both include RAC1 and involved fusion and fission processes ( 43 ) (Fig. 4 B ).…”

Section: Resultsmentioning

confidence: 99%

“…(51) Network analysis also identified genes related to potential osteoclast-immune cell interactions, such as the ICOS-ICOSL pathway, (52) and genes involved in fusion and fission processes. (43,44) Based on this network analysis, we further complemented the phenotype of osteoclasts by analyzing the expression of the target genes of the miRs of interest, as well as certain genes associated with related pathways, such as mTOR signaling and immune cell-osteoclast interplay as mentioned above.…”

Section: Discussionmentioning

confidence: 99%

“…4A). Direct targets of the selected 5 miRs of interest include RAC1, involved in membrane protrusions; (43) for only miR-193b-3p, SLC1A5, encoding syncytin-1 receptor involved in osteoclast fusion; (11) and NF1, encoding RasGAP Neurofibromin, involved in the fission process. (44) In addition, we carried out enrichment analysis of the GO and KEGG metabolic pathways.…”

Section: Impact Of Mir Inhibition On Osteoclast Multinucleation and B...mentioning

confidence: 99%

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Osteoclast microRNA Profiling in Rheumatoid Arthritis to Capture the Erosive Factor

Hoang Dong,

Audrey,

Leopold

et al. 2023

JBMR Plus

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In rheumatoid arthritis (RA), only a subset of patients develop irreversible bone destruction. Our aim was to identify a microRNA (miR)‐based osteoclast‐related signature predictive of erosiveness in RA. Seventy‐six adults with erosive (E) or nonerosive (NE) seropositive RA and 43 sex‐ and age‐matched healthy controls were recruited. Twenty‐five miRs from peripheral blood mononuclear cell (PBMC)‐derived osteoclasts selected from RNA‐Seq (discovery cohort) were assessed by qPCR (replication cohort), as were 33 target genes (direct targets or associated with regulated pathways). The top five miRs found differentially expressed in RA osteoclasts were either decreased (hsa‐miR‐34a‐3p, 365b‐3p, 374a‐3p, and 511‐3p [E versus NE]) or increased (hsa‐miR‐193b‐3p [E versus controls]). In vitro, inhibition of miR‐34a‐3p had an impact on osteoclast bone resorption. An integrative network analysis of miRs and their targets highlighted correlations between mRNA and miR expression, both negative (CD38, CD80, SIRT1) and positive (MITF), and differential gene expression between NE versus E (GXYLT1, MITF) or versus controls (CD38, KLF4). Machine‐learning models were used to evaluate the value of miRs and target genes, in combination with clinical data, to predict erosion. One model, including a set of miRs (predominantly 365b‐3p) combined with rheumatoid factor titer, provided 70% accuracy (area under the curve [AUC] 0.66). Adding genes directly targeted or belonging to related pathways improved the predictive power of the model for the erosive phenotype (78% accuracy, AUC 0.85). This proof‐of‐concept study indicates that identification of RA subjects at risk of erosions may be improved by studying miR expression in PBMC‐derived osteoclasts, suggesting novel approaches toward personalized treatment. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Impact Of Mir Inhibition On Osteoclast Multinucleation and B...mentioning

confidence: 99%

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Osteoclast microRNA Profiling in Rheumatoid Arthritis to Capture the Erosive Factor

Hoang Dong,

Audrey,

Leopold

et al. 2023

JBMR Plus

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“…Second, we show that RhoA signaling stimulates primordium motility through two distinct processes: at the tip of protrusions, RhoA signaling promotes actin polymerization, and at the base of protrusions, RhoA signaling activates myosin II to pull the F-actin network rearward and retract protrusions. These roles for RhoA that also have been recently identified in cultured cells (Azoitei et al, 2019;Hu et al, 2022;Lee et al, 2015;Machacek et al, 2009;Martin et al, 2016;Pertz et al, 2006;Tkachenko et al, 2011;Yang et al, 2015). Together, these RhoA activities generate rearward directed actin flow that is then transmitted -partly through integrins (Yamaguchi et al, 2022) -to the substrate and propels the primordium forward.…”

Section: The Primordium Generates Traction On the Basement Membrane T...mentioning

confidence: 71%

Pulses of RhoA Signaling Stimulate Actin Polymerization and Flow in Protrusions to Drive Collective Cell Migration

Qian,

Yamaguchi,

Lis

et al. 2023

Preprint

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SummaryIn animals, cells often move as collectives to shape organs, close wounds, or—in the case of disease—metastasize. To accomplish this, cells need to generate force to propel themselves forward. The motility of singly migrating cells is driven largely by an interplay between Rho GTPase signaling and the actin network (Yamada and Sixt, 2019). Whether cells migrating as collectives use the same machinery for motility is unclear. Using the zebrafish posterior lateral line primordium as a model for collective cell migration, we find that active RhoA and myosin II cluster on the basal sides of the primordium cells and are required for primordium motility. Positive and negative feedbacks cause RhoA and myosin II activities to pulse. These pulses of RhoA signaling stimulate actin polymerization at the tip of the protrusions and myosin II-dependent actin flow and protrusion retraction at the base of the protrusions, and deform the basement membrane underneath the migrating primordium. This suggests that RhoA-induced actin flow on the basal sides of the cells constitutes the motor that pulls the primordium forward, a scenario that likely underlies collective migration in other—but not all (Bastock and Strutt, 2007; Lebreton and Casanova, 2013; Matthews et al., 2008)—contexts.

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“…Cells employ small GTPases to regulate their cytoskeleton, with the coordination of Rac1 and RhoA GTP-bound activities governing protrusion and retraction initiation and reinforcement ( 31 – 33 ). This careful balance in activity is essential for efficient cell migration and spreading ( 34 , 35 ) and is often regulated by integrin-mediated signaling ( 36 ).…”

Section: Resultsmentioning

confidence: 99%

Defined extracellular matrix compositions support stiffness-insensitive cell spreading and adhesion signaling

Conway,

Isomursu,

Follain

et al. 2023

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

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Integrin-dependent adhesion to the extracellular matrix (ECM) mediates mechanosensing and signaling in response to altered microenvironmental conditions. In order to provide tissue- and organ-specific cues, the ECM is composed of many different proteins that temper the mechanical properties and provide the necessary structural diversity. Despite most human tissues being soft, the prevailing view from predominantly in vitro studies is that increased stiffness triggers effective cell spreading and activation of mechanosensitive signaling pathways. To address the functional coupling of ECM composition and matrix rigidity on compliant substrates, we developed a matrix spot array system to screen cell phenotypes against different ECM mixtures on defined substrate stiffnesses at high resolution. We applied this system to both cancer and normal cells and surprisingly identified ECM mixtures that support stiffness-insensitive cell spreading on soft substrates. Employing the motor-clutch model to simulate cell adhesion on biochemically distinct soft substrates, with varying numbers of available ECM–integrin–cytoskeleton (clutch) connections, we identified conditions in which spreading would be supported on soft matrices. Combining simulations and experiments, we show that cell spreading on soft is supported by increased clutch engagement on specific ECM mixtures and even augmented by the partial inhibition of actomyosin contractility. Thus, “stiff-like” spreading on soft is determined by a balance of a cell’s contractile and adhesive machinery. This provides a fundamental perspective for in vitro mechanobiology studies, identifying a mechanism through which cells spread, function, and signal effectively on soft substrates.

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Local temporal Rac1-GTP nadirs and peaks restrict cell protrusions and retractions

Cited by 8 publications

References 57 publications

Osteoclast microRNA Profiling in Rheumatoid Arthritis to Capture the Erosive Factor

Osteoclast microRNA Profiling in Rheumatoid Arthritis to Capture the Erosive Factor

Pulses of RhoA Signaling Stimulate Actin Polymerization and Flow in Protrusions to Drive Collective Cell Migration

Defined extracellular matrix compositions support stiffness-insensitive cell spreading and adhesion signaling

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