title: Mechanoaccumulative Elements of the Mammalian Actin Cytoskeleton.
abstract: 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.
authors.affiliation: Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Schiffhauer
authors.affiliation: Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA.
authors.forename: Tianzhi
authors.initials: T
authors.lastname: Luo
authors.affiliation: Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
authors.forename: Krithika
authors.initials: K
authors.lastname: Mohan
authors.affiliation: Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
authors.forename: Vasudha
authors.initials: V
authors.lastname: Srivastava
authors.affiliation: Department of Biomedical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
authors.forename: Xuyu
authors.initials: X
authors.lastname: Qian
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Griffis
authors.affiliation: Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA.|Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.|Department of Biomedical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Iglesias
authors.affiliation: Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA.|Department of Pharmacology and Molecular Science, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA.|Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
authors.forename: Douglas N
authors.initials: DN
authors.lastname: Robinson
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000185:Actinin / Q000378:metabolism*; D000818:Animals; D064448:Filamins / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D024462:Myosin Type II / Q000378:metabolism*; D041681:NIH 3T3 Cells
chemical_list: D064448:Filamins; D000185:Actinin; D024462:Myosin Type II