α-Actinin-4 Is Required for Amoeboid-type Invasiveness of Melanoma Cells

Shao, Hanshuang; Li, Shaoyan; Watkins, Simon C.; Wells, Alan

doi:10.1074/jbc.m114.579185

Cited by 38 publications

(39 citation statements)

References 41 publications

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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

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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Section: Resultsmentioning

confidence: 99%

Mechanoaccumulative Elements of the Mammalian Actin Cytoskeleton

Schiffhauer

Luo²,

Mohan

et al. 2017

Biophysical Journal

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“…Tenascin and other proteins are mainly at the edge of the advancing wound front wherein they establish a pro-migratory environment, serving also to enhance inflammatory cell adhesion and migration early in the healing process (28). These matricellular proteins in turn effect growth factor signaling through cryptic receptor binding motifs within the proteins themselves (matrikines), which signal via the EGF receptor to induce motility (15, 29–31) In the same vein, these components also may contain growth factor binding sites that similarly regulate signaling, such as those found in fibronectin (32). As the fibroblasts immigrate and establish in the wound site, they produce collagen III and collagen I to provide further structural integrity to the matrix, with fibronectin acting in this important case as a scaffold for collagen deposition (33).…”

Section: A Changing Matrix During Repair and Regenerationmentioning

confidence: 99%

Skin tissue repair: Matrix microenvironmental influences

2016

Self Cite

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The process of repair of wounded skin involves intricate orchestration not only between the epidermal and dermal compartments but also between the resident and immigrant cells and the local microenvironment. Only now are we beginning to appreciate the complex roles played by the matrix in directing the outcome of the repair processes, and how this impacts the signals from the various cells. Recent findings speak of dynamic and reciprocal interactions that occurs among the matrix, growth factors, and cells that underlies this integrated process. Further confounding this integration are the physiologic and pathologic situations that directly alter the matrix to impart at least part of the dysrepair that occurs. These topics will be discussed with a call for innovative model systems of direct relevance to the human situation.

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“…ACTN4, for example, plays multiple roles in influencing cellular morphology, yet the mechanisms by which it contributes to increased cancer invasion has not been resolved. Previous studies found that ACTN4 plays a major role in destabilizing focal adhesions in multiple cell types [34, 35]. The focal adhesion protein zyxin binds to the rod domain of ACTN4 and recruits it to nascent focal adhesions [26].…”

Section: Alpha-actinin In Metastatic Cancermentioning

confidence: 99%

“…The focal adhesion protein zyxin binds to the rod domain of ACTN4 and recruits it to nascent focal adhesions [26]. Overexpression of ACTN4 in melanoma cancer cell lines drives cellular morphology from a more mesenchymal type to an amoeboid type by reducing focal adhesion size [35]. In ACTN4 knockdown mouse fibroblasts, focal adhesions are fewer, yet larger, and spreading is increased, consistent with mesenchymal type cells [36].…”

Section: Alpha-actinin In Metastatic Cancermentioning

confidence: 99%

“…Amoeboid cells lack stress fibers, and instead use high myosin II-mediated contraction in the cell cortex which drives the cell to invade through a blebbing mechanism [38]. The amoeboid phenotype of ACTN4-overexpressing cells [35] might explain their dramatic increase in invasion and metastasis through the dense stroma of tumors. Understanding this alteration and enhancement of invasion remains critical to developing therapeutics to mitigate metastasis, and ACTN4 presents itself as an intriguing target.…”

Section: Alpha-actinin In Metastatic Cancermentioning

confidence: 99%

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The fifth sense: Mechanosensory regulation of alpha-actinin-4 and its relevance for cancer metastasis

Thomas

Robinson

2017

Seminars in Cell & Developmental Biology

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Metastatic cancer cells invading through dense tumor stroma experience internal and external forces that are sensed through a variety of mechanosensory proteins that drive adaptations for specific environments. Alpha-actinin-4 (ACTN4) is a member of the α-actinin family of actin crosslinking proteins that is upregulated in several types of cancers. It shares 86% protein similarity with α-actinin-1, another non-muscle ACTN isoform, which appears to have a more modest role, if any, in cancer progression. While they share regulatory mechanisms, such as phosphorylation, calcium binding, phosphatidyl inositol binding, and calpain cleavage, α-actinin- 4 exhibits a unique mechanosensory regulation that α-actinin-1 does not. This behavior is mediated, at least in part, by each protein’s actin-binding affinity as well as the catch-slip-bond behavior of the actin binding domains. We will discuss currently known modes of ACTN4 regulation, their interactions, and how mechanosensation may provide major therapeutic targeting potential for cancer metastasis.

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α-Actinin-4 Is Required for Amoeboid-type Invasiveness of Melanoma Cells

Cited by 38 publications

References 41 publications

Mechanoaccumulative Elements of the Mammalian Actin Cytoskeleton

Mechanoaccumulative Elements of the Mammalian Actin Cytoskeleton

Skin tissue repair: Matrix microenvironmental influences

The fifth sense: Mechanosensory regulation of alpha-actinin-4 and its relevance for cancer metastasis

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