Filamin B Enhances the Invasiveness of Cancer Cells into 3D Collagen Matrices

Iguchi, Y; Ishihara, Seiichiro; Uchida, Yuka; Tajima, K.; Mizutani, Takeomi; Kawabata, Kazushige; Haga, Hisashi

doi:10.1247/csf.15001

“…For example, mechanotransducing stress fibers, which dynamically form and dissolve during cell migration, are crosslinked largely by α-actinins and therefore could become more stable via α-actinin catch-bonding under load [36, 37]. In addition to genetic diseases related to filamin B and α-actinin 4 mutations [38, 39], increased expression of the mechanosensitive paralogs of α-actinin and filamin are strong negative prognosticators in multiple metastatic cancers [40-42]. Defining the mechanisms by which individual proteins and the network as a whole respond to force and determining which cytoskeletal elements are mechanosensitive is essential for elucidating normal mechanosensitive biological processes and identifying new targets for inhibiting aberrant processes in disease states.…”

Section: Resultsmentioning

confidence: 99%

Mechanoaccumulative Elements of the Mammalian Actin Cytoskeleton

Schiffhauer

¹

,

Luo

²

,

Mohan

³

et al. 2016

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To change shape, divide, form junctions, and migrate, cells reorganize their cytoskeletons in response to changing mechanical environments [1-4]. Actin cytoskeletal elements, including myosin II motors and actin crosslinkers, structurally remodel and activate signaling pathways in response to imposed stresses [5-9]. Recent studies demonstrate the importance of force-dependent structural rearrangement of α-catenin in adherens junctions [10] and vinculin's molecular clutch mechanism in focal adhesions [11]. However, the complete landscape of cytoskeletal mechanoresponsive proteins and the mechanisms by which these elements sense and respond to force remain to be elucidated. To find mechanosensitive elements in mammalian cells, we examined protein relocalization in response to controlled external stresses applied to individual cells. Here, we show that non-muscle myosin II, α-actinin, and filamin accumulate to mechanically stressed regions in cells from diverse lineages. Using reaction-diffusion models for force-sensitive binding, we successfully predicted which mammalian α-actinin and filamin paralogs would be mechanoaccumulative. Furthermore, a Goldilocks zone must exist for each protein where the actin-binding affinity must be optimal for accumulation. In addition, we leveraged genetic mutants to gain a molecular understanding of the mechanisms of α-actinin and filamin catch-bonding behavior. Two distinct modes of mechanoaccumulation can be observed: a fast, diffusion-based accumulation and a slower, myosin II-dependent cortical flow phase that acts on proteins with specific binding lifetimes. Finally, we uncovered cell-type and cell-cycle-stage-specific control of the mechanosensation of myosin IIB, but not myosin IIA or IIC. Overall, these mechanoaccumulative mechanisms drive the cell's response to physical perturbation during proper tissue development and disease.

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“…For example, mechanotransducing stress fibers, which dynamically form and dissolve during cell migration, are crosslinked largely by α-actinins and therefore could become more stable via α-actinin catch-bonding under load [36,37]. In addition to genetic diseases related to filamin B and α-actinin 4 mutations [ 38 , 39], increased expression of the mechanosensitive paralogs of α-actinin and filamin are strong negative prognosticators in multiple metastatic cancers [40][41][42]. Defining the mechanisms by which individual proteins and the network as a whole respond to force and determining which cytoskeletal elements are mechanosensitive is essential for elucidating normal mechanosensitive biological processes and identifying new targets for inhibiting aberrant processes in disease states.…”

Section: Resultsmentioning

confidence: 99%

Mechanoaccumulative Elements of the Mammalian Actin Cytoskeleton

Schiffhauer

¹

,

Luo²,

Mohan

³

et al. 2017

Biophysical Journal

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To change shape, divide, form junctions, and migrate, cells reorganize their cytoskeletons in response to changing mechanical environments [ 1 -4 ]. Actin cytoskeletal elements, including myosin II motors and actin crosslinkers, structurally remodel and activate signaling pathways in response to imposed stresses [5][6][7][8][9]. Recent studies demonstrate the importance of force-dependent structural rearrangement of α-catenin in adherens junctions [ 10 ] and vinculin's molecular clutch mechanism in focal adhesions [ 11 ]. However, the complete landscape of cytoskeletal mechanoresponsive proteins and the mechanisms by which these elements sense and respond to Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Author Contributions E.S.S., T.L., E.G., V.S., and D.N.R. conceived experiments. E.S.S., T.L., V.S. and X.Q. performed experiments. K.M. and P.A.I. developed the model and carried out the simulations. E.S.S. and T.L. wrote the manuscript, V.S., K.M., E.G., P.A.I., and D.N.R. edited the manuscript. , Tables S1 and S2, Figures S1-S4, and Supplemental References. Supplementary Information Supplemental Information includes Supplemental Materials and Procedures HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript force remain to be elucidated. To find mechanosensitive elements in mammalian cells, we examined protein relocalization in response to controlled external stresses applied to individual cells. Here, we show that non-muscle myosin II, α-actinin, and filamin accumulate to mechanically stressed regions in cells from diverse lineages. Using reaction-diffusion models for force-sensitive binding, we successfully predicted which mammalian α-actinin and filamin paralogs would be mechanoaccumulative. Furthermore, a Goldilocks zone must exist for each protein where the actin-binding affinity must be optimal for accumulation. In addition, we leveraged genetic mutants to gain a molecular understanding of the mechanisms of α-actinin and filamin catch-bonding behavior. Two distinct modes of mechanoaccumulation can be observed: a fast, diffusion-based accumulation and a slower, myosin II-dependent cortical flow phase that acts on proteins with specific binding lifetimes. Finally, we uncovered cell-type and cell-cycle-stagespecific control of the mechanosensation of myosin IIB, but not myosin IIA or IIC. Overall, these mechanoaccumulative mechanisms drive the cell's response to physical perturbation during proper tissue development and disease. Results and DiscussionTo identify mechanosensitive elements, we examined protein relocalization i...

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“…We performed time-lapse imaging for cell tracking and evaluated invasion speed using previously reported methods [13].…”

mentioning

confidence: 99%

Role of ATF5 in the invasive potential of diverse human cancer cell lines

Nukuda

¹

,

Endoh

²

,

Yasuda

³

et al. 2016

Biochemical and Biophysical Research Communications

Self Cite

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Activating transcription factor 5 (ATF5) is a member of the ATF/cAMP response element-binding protein family. Our research group recently revealed that ATF5 expression increases the invasiveness of human lung carcinoma cells. However, the effects of ATF5 on the invasive potential of other cancer cells lines remain unclear.Therefore, in this study, we investigated the role of ATF5 in the invasive activity of diverse human cancer cell lines. Invasiveness was assessed using Matrigel invasion assays. ATF5 knockdown resulted in decreased invasiveness in seven of eight cancer cell lines tested. These results suggest that ATF5 promotes invasiveness in several cancer cell lines. Furthermore, the roles of ATF5 in the invasiveness were evaluated in three-dimensional (3D) culture conditions. In 3D collagen gel, HT-1080 and MDA-MB-231 cells exhibited high invasiveness, with spindle morphology and high invasion speed. In both cell lines, knockdown of ATF5 resulted in rounded morphology and decreased invasion speed. Next, we showed that ATF5 induced integrin-2 and integrin-1 expression and that the depletion of integrin-2 or integrin-1 resulted in round morphology and decreased invasion speed. Our results suggest that ATF5 promotes invasion by inducing the expression of integrin-2 and integrin-1 in several 3 human cancer cell lines. ATF5 regulates cell morphology in a 3D collagen gel via integrin-21 activity. Keywords

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Filamin B Enhances the Invasiveness of Cancer Cells into 3D Collagen Matrices

Cited by 30 publications

References 25 publications

Mechanoaccumulative Elements of the Mammalian Actin Cytoskeleton

Mechanoaccumulative Elements of the Mammalian Actin Cytoskeleton

Mechanoaccumulative Elements of the Mammalian Actin Cytoskeleton

Role of ATF5 in the invasive potential of diverse human cancer cell lines

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