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α-Actinin-4 drives invasiveness by regulating myosin IIB expression and myosin IIA localization
Open accessPublished version of a preprint
Abstract
The mechanisms by which the mechanoresponsive actin crosslinking protein α-actinin-4 (ACTN4) regulates cell motility and invasiveness remain incompletely understood. Here, we show that, in addition to regulating protrusion dynamics and focal adhesion formation, ACTN4 transcriptionally regulates expression of non-muscle myosin IIB (NMM IIB; heavy chain encoded by MYH10), which is essential for mediating nuclear translocation during 3D invasion. We further show that an indirect association between ACTN4 and NMM IIA (heavy chain encoded by MYH9) mediated by a functional F-actin cytoskeleton is essential for retention of NMM IIA at the cell periphery and modulation of focal adhesion dynamics. A protrusion-dependent model of confined migration recapitulating experimental observations predicts a dependence of protrusion forces on the degree of confinement and on the ratio of nucleus to matrix stiffness. Together, our results suggest that ACTN4 is a master regulator of cancer invasion that regulates invasiveness by controlling NMM IIB expression and NMM IIA localization. This article has an associated First Person interview with the first author of the paper.
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Self-citation
Metadata
- Authors
- Barai, A., Mukherjee, A., Das, A., Saxena, N., & Sen, S.
- Affiliations
- Indian Institute of Technology Bombay (IN)
- Corresponding author
- Barai, Amlan
- Sen, Shamik
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2021-12-01
- Volume
- 134
- Issue
- 23
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W3210454758
- Cited by
- 23
- References
- 65
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 7 · 2023: 1 · 2022: 4 · 2021: 1
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cell Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Department of Science and Technology, Ministry of Science and Technology, India (DST/SJF/LSA-01/2016-17)
- Department of Biotechnology, Ministry of Science and Technology, India (BT/PR32927/MED/30/2195/2020)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- ACTN4, myosin IIB, myosin IIA, tumor invasion, cell motility, focal adhesions, actin cytoskeleton, nuclear translocation, confined migration, extracellular matrix stiffness, transcriptional regulation, mechanotransduction
- MeSH terms
- Actinin, Actins, Cell Movement, Humans, Myosin Heavy Chains, Nonmuscle Myosin Type IIB, Nonmuscle Myosin Type IIA
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