Predicting how cells spread and migrate

Kim, Dong Hwee; Wirtz, Denis

doi:10.4161/cam.24804

Cited by 71 publications

(66 citation statements)

References 38 publications

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“…Cell motility requires the transmission of force through focal adhesions, and focal adhesion size has been shown to correlate directly with cell velocity (44). Therefore, the effect of focal adhesions on cell velocity induced by hypoxia was investigated by generating MDA-MB-231 subclones stably transfected with shEV vector or a vector encoding either of two independent shRNAs targeting FAK (Fig.…”

Section: Focal Adhesions Are Required For Enhanced Cell Motility Undermentioning

confidence: 99%

RETRACTED: Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells

Gilkes

Xiang²,

Lee³

et al. 2013

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

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181

171

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Overexpression of Rho kinase 1 (ROCK1) and the G protein RhoA is implicated in breast cancer progression, but oncogenic mutations are rare, and the molecular mechanisms that underlie increased ROCK1 and RhoA expression have not been determined. RhoAbound ROCK1 phosphorylates myosin light chain (MLC), which is required for actin-myosin contractility. RhoA also activates focal adhesion kinase (FAK) signaling. Together, these pathways are critical determinants of the motile and invasive phenotype of cancer cells. We report that hypoxia-inducible factors coordinately activate RhoA and ROCK1 expression and signaling in breast cancer cells, leading to cell and matrix contraction, focal adhesion formation, and motility through phosphorylation of MLC and FAK. Thus, intratumoral hypoxia acts as an oncogenic stimulus by triggering hypoxia-inducible factor → RhoA → ROCK1 → MLC → FAK signaling in breast cancer cells.cytoskeletal reprogramming | metastasis | migration | oxygen | tumor microenvironment I nvasion and metastasis are complex processes leading to dissemination of cancer cells from the primary tumor to distant organs. A critical step is cytoskeletal reprogramming, which transforms rigid, immobile epithelial cells to motile, invasive cancer cells. Members of the Rho family of GTPases play a central role in this process by functioning as molecular switches that control morphogenesis and movement (1). Rho proteins mediate both polymerization of actin (F-actin formation) to create stress fibers, which are antiparallel actin filaments that are crosslinked by myosin, and activation of myosin to trigger contractility (2, 3). Active (GTP-loaded) Rho binds to Rho-associated coiled-coilforming kinase (ROCK), resulting in activation of the kinase (4). This activation mediates the phosphorylation of myosin light chain (MLC) directly as well as indirectly by inhibiting myosin phosphatase (MYPT), leading to actin-myosin contraction (5, 6). ROCK also phosphorylates LIM kinase, which inhibits actin depolymerization (7).For cells to move, force generated by actin-myosin contractility is used to pull on the extracellular matrix (ECM) at focal adhesions, and ECM stiffness promotes the formation of focal adhesions (8). Conversely, substrate stiffness is induced by cell contraction and leads to the activation of focal adhesion kinase (FAK), which is required for mechanosensing and cell motility (9-11). A positive regulatory loop exists between Rho family member A (RhoA) and FAK signaling. In mouse models, FAK plays a critical role in breast cancer progression (12, 13).ROCK1 and RHOA gene expression are coordinately up-regulated in motile cells isolated from metastatic breast cancers (14). Clinical and experimental data indicate that increased expression of RhoA or ROCK1 is associated with breast cancer progression (15)(16)(17)(18)(19). Somatic mutations do not account for RhoA or ROCK1 overexpression in the majority of breast cancers, and the underlying molecular mechanisms remain undefined.The presence of intratumoral hypoxia, i.e., ...

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Section: Focal Adhesions Are Required For Enhanced Cell Motility Undermentioning

confidence: 99%

RETRACTED: Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells

Gilkes

Xiang²,

Lee³

et al. 2013

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

Self Cite

181

171

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“…Although cytoskeleton is important for cell shape and their spreading on ECM matrix (57), the extent and size of the focal adhesion complex will dictate the robustness in adhesion of cells on the surfaces (58). Our data showed that although no drastic differences were observed in the pattern of stress fibers visualized by F-actin staining, a difference in FAK staining was observed in cells attached on collagen and amyloid surfaces (Fig.…”

Section: Resultsmentioning

confidence: 41%

Cell Adhesion on Amyloid Fibrils Lacking Integrin Recognition Motif

Jacob¹,

George²,

Singh

et al. 2016

Journal of Biological Chemistry

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Amyloids are highly ordered, cross-␤-sheet-rich protein/peptide aggregates associated with both human diseases and native functions. Given the well established ability of amyloids in interacting with cell membranes, we hypothesize that amyloids can serve as universal cell-adhesive substrates. Here, we show that, similar to the extracellular matrix protein collagen, amyloids of various proteins/peptides support attachment and spreading of cells via robust stimulation of integrin expression and formation of integrin-based focal adhesions. Additionally, amyloid fibrils are also capable of immobilizing non-adherent red blood cells through charge-based interactions. Together, our results indicate that both active and passive mechanisms contribute to adhesion on amyloid fibrils. The present data may delineate the functional aspect of cell adhesion on amyloids by various organisms and its involvement in human diseases. Our results also raise the exciting possibility that cell adhesivity might be a generic property of amyloids.

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“…Immunofluorescence measurements of vinculin, a component of the FA complex, revealed a significant increase in the average area of FAs in FL2-depleted U2OS cells compared to controls (0.87±0.07 m 2 in controls vs. 2.54±0.18 m 2 in FL2 siRNA-treated cells; Figure 3 c and d). Though FA area has long been thought to negatively correlate with migration speed (Gardel et al 2011), recent reports have identified a biphasic relationship in which cells move faster with increased FA area up to a threshold point, beyond which cell migration slows down (Kim and Wirtz 2013a, 2013b). Strikingly, the average area of FAs in FL2 depleted cells, 2.54µm 2 , is almost identical to the FA area shown by Kim and Wirtz to correlate with the fastest migration speed in fibroblasts (Kim and Wirtz 2013a).…”

Section: Resultsmentioning

confidence: 99%

Fidgetin-Like 2: A Microtubule-Based Regulator of Wound Healing

Charafeddine

Makdisi

Schairer

et al. 2015

Journal of Investigative Dermatology

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Wound healing is a complex process driven largely by the migration of a variety of distinct cell types from the wound margin into the wound zone. In this study, we identify the previously uncharacterized microtubule-severing enzyme, Fidgetin-like 2 (FL2), as a fundamental regulator of cell migration that can be targeted in vivo using nanoparticle-encapsulated siRNA to promote wound closure and regeneration. In vitro, depletion of FL2 from mammalian tissue culture cells results in a more than two-fold increase in the rate of cell movement, due in part to a significant increase in directional motility. Immunofluorescence analyses indicate that FL2 normally localizes to the cell edge, importantly to the leading edge of polarized cells, where it regulates the organization and dynamics of the microtubule cytoskeleton. To clinically translate these findings, we utilized a nanoparticle-based siRNA delivery platform to locally deplete FL2 in both murine full-thickness excisional and burn wounds. Topical application of FL2 siRNA nanoparticles to either wound type results in a significant enhancement in the rate and quality of wound closure both clinically and histologically relative to controls. Taken together, these results identify FL2 as a promising therapeutic target to promote the regeneration and repair of cutaneous wounds.

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Predicting how cells spread and migrate

Abstract: CoMMentAryCommentary to: Kim DH, Wirtz D. Focal adhesion size uniquely predicts cell migration. FASEB J 2013; 27:1351-61

Cited by 71 publications

References 38 publications

RETRACTED: Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells

RETRACTED: Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells

Cell Adhesion on Amyloid Fibrils Lacking Integrin Recognition Motif

Fidgetin-Like 2: A Microtubule-Based Regulator of Wound Healing

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