A mechanosensory system governs myosin II accumulation in dividing cells

Kee, Yee Seir; Ren, Yixin; Dorfman, Danielle; Iijima, Miho; Firtel, Richard A.; Iglesias, Pablo A.; Robinson, Douglas N.

doi:10.1091/mbc.e11-07-0601

Cited by 59 publications

(132 citation statements)

References 62 publications

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“…However, in vitro motility assays only probe the rate-limiting step for motility under no-load conditions. In vivo, myosin II experiences load in the context of a mechanosensory control system anchored, in part, by its cooperative interaction with another actin cross-linker, cortexillin I (21,22). If we interrupt this control system by deleting cortexillin I, 4-HAP-directed myosin II accumulation is also abolished (Fig.…”

Section: Resultsmentioning

confidence: 99%

Pharmacological activation of myosin II paralogs to correct cell mechanics defects

Surcel¹,

Ng²,

West‐Foyle³

et al. 2015

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

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Current approaches to cancer treatment focus on targeting signal transduction pathways. Here, we develop an alternative system for targeting cell mechanics for the discovery of novel therapeutics. We designed a live-cell, high-throughput chemical screen to identify mechanical modulators. We characterized 4-hydroxyacetophenone (4-HAP), which enhances the cortical localization of the mechanoenzyme myosin II, independent of myosin heavy-chain phosphorylation, thus increasing cellular cortical tension. To shift cell mechanics, 4-HAP requires myosin II, including its full power stroke, specifically activating human myosin IIB (MYH10) and human myosin IIC (MYH14), but not human myosin IIA (MYH9). We further demonstrated that invasive pancreatic cancer cells are more deformable than normal pancreatic ductal epithelial cells, a mechanical profile that was partially corrected with 4-HAP, which also decreased the invasion and migration of these cancer cells. Overall, 4-HAP modifies nonmuscle myosin II-based cell mechanics across phylogeny and disease states and provides proof of concept that cell mechanics offer a rich drug target space, allowing for possible corrective modulation of tumor cell behavior. mechanical modulator | 3,4-dichloroaniline | 4-hydroxyacetophenone | myosin II | pancreatic cancer C ell shape change processes include cell growth, division, motility, and the formation of complex structures like tissues and organs, all of which are governed by the intersection of biochemistry, genetics, and mechanics. These three modules are integral not just for normal function in healthy cells but also in disease states. Pharmacological manipulation of some of these modules has already led to treatment strategies for inflammation and cancer (e.g., paclitaxel) (1, 2). However, many presently available therapies, which address only one aspect of cell shape change, typically either fail to abolish the disease completely or lead to compensatory regulatory changes, and therefore to drug resistance. Targeting cell mechanics remains an underused approach for drug development. In cancer, altered cell mechanics are a hallmark of metastatic efficiency: cell stiffness decreases up to 70% in many metastatic cancer cells (3-5). It is rational then that one therapeutic approach is to increase cellular elasticity, which would, in turn, reduce metastatic potential and act downstream of cancer-inducing genetic alterations.Known mechanical modulators (e.g., latrunculin, blebbistatin) are often lethal, have numerous off-site targets, and act to generate a softer and metastatic-like mechanical phenotype (6, 7). However, the field's ability to increase cellular elasticity on acute time scales is highly restricted. In an effort to close this gap and find modulators that stiffen cells, we leveraged our molecular and analytical understanding of cytokinesis, an evolutionarily conserved and highly mechanical cell shape change event, to establish an in vivo, large-scale, high-throughput chemical screen for small-molecule modulators of cell shap...

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Section: Resultsmentioning

confidence: 99%

Pharmacological activation of myosin II paralogs to correct cell mechanics defects

Surcel¹,

Ng²,

West‐Foyle³

et al. 2015

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

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“…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 ].…”

mentioning

confidence: 99%

Mechanoaccumulative Elements of the Mammalian Actin Cytoskeleton

Schiffhauer

Luo²,

Mohan

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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“…This cooperative accumulation can account quantitatively for myosin and cortexillin I accumulation in response to mechanical stress (41). Further, this cooperative accumulation can account for the insertion of myosin II into the cortex of the cleavage furrow, where it promotes additional accumulation of kinesin 6 (Kif12) and INCENP through the cortexillin I-binding IQGAP2 (GapA) (46) (Fig. 2).…”

Section: Chemical and Mechanical Inputs Direct Shape Changementioning

confidence: 96%

“…2). Thus, the cleavage furrow cortex comprises a mechanochemical feedback loop where both chemical and mechanical signals promote accumulation of the appropriate machinery (46,47). This system is inherently quite robust: the network of cytokinesis cytoskeletal machinery stabilizes under mechanical load in a manner that is independent of any single protein (22).…”

Section: Chemical and Mechanical Inputs Direct Shape Changementioning

confidence: 99%

“…During cytokinesis, Dictyostelium myosin II is likely capable of achieving a 30-to 50-fold dynamic range in force production through a 3-to 5-fold increase from accumulation of myosin II at the furrow by chemical and mechanical signals (46), and a 5-to 8-fold increase in the duty ratio under applied load. This 5-to 8-fold increase due to a shift in the duty ratio assumes that Dictyostelium myosin II exhibits a force-dependent duty ratio similar to that observed for mammalian nonmuscle myosin II (42) (Fig.…”

Section: Mechanochemical Signaling Allows Dynamic Escalation Of Forcementioning

confidence: 99%

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Mechanochemical Signaling Directs Cell-Shape Change

Schiffhauer

Robinson

2017

Biophysical Journal

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For specialized cell function, as well as active cell behaviors such as division, migration, and tissue development, cells must undergo dynamic changes in shape. To complete these processes, cells integrate chemical and mechanical signals to direct force production. This mechanochemical integration allows for the rapid production and adaptation of leading-edge machinery in migrating cells, the invasion of one cell into another during cell-cell fusion, and the force-feedback loops that ensure robust cytokinesis. A quantitative understanding of cell mechanics coupled with protein dynamics has allowed us to account for furrow ingression during cytokinesis, a model cell-shape-change process. At the core of cell-shape changes is the ability of the cell's machinery to sense mechanical forces and tune the force-generating machinery as needed. Force-sensitive cytoskeletal proteins, including myosin II motors and actin cross-linkers such as a-actinin and filamin, accumulate in response to internally generated and externally imposed mechanical stresses, endowing the cell with the ability to discern and respond to mechanical cues. The physical theory behind how these proteins display mechanosensitive accumulation has allowed us to predict paralogspecific behaviors of different cross-linking proteins and identify a zone of optimal actin-binding affinity that allows for mechanical stress-induced protein accumulation. These molecular mechanisms coupled with the mechanical feedback systems ensure robust shape changes, but if they go awry, they are poised to promote disease states such as cancer cell metastasis and loss of tissue integrity.The concept ''form begets function begets form'' provides an excellent foundation for understanding the behavior of biological systems. Even specialized cells, the smallest unit of complex living systems, perform all of the necessary functions of an organism by assuming distinct shapes, mechanical properties, and physical behaviors. Different cell types use a common set of cytoskeletal elements to provide precise physical support for their distinct functions. For example, red blood cells and neurons have very different shapes that allow them to perform their specific roles. However, they both utilize alternating patterns of actin and spectrin to form cortices with appropriate viscous and elastic properties, albeit in different structural arrangements. Perturbations to this structural network cause a breakdown in the mechanical properties, or the form, of these cells, which inhibits cell function (1,2).Fascinatingly, the physical properties of cells are both determined and acted upon by the cytoskeletal apparatus. Cells are capable of modifying their own physical properties and driving changes in cell shape in response to internal and external chemical and mechanical stimuli. These modifications occur through the remodeling of the cell cortex, the network of cytoskeletal proteins directly under the plasma membrane. Much progress has been made recently in deciphering how chemical signa...

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A mechanosensory system governs myosin II accumulation in dividing cells

Abstract: A mechanosensory system is characterized that fine-tunes the level of myosin II at the cleavage furrow. This mechanosensory system consists of the mechanosensory module composed of myosin II and cortexillin I and a mechanotransduction loop that includes IQGAP2, kinesin-6, and INCENP.

Cited by 59 publications

References 62 publications

Pharmacological activation of myosin II paralogs to correct cell mechanics defects

Pharmacological activation of myosin II paralogs to correct cell mechanics defects

Mechanoaccumulative Elements of the Mammalian Actin Cytoskeleton

Mechanochemical Signaling Directs Cell-Shape Change

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