Key Points
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Numerous cell surface receptors modulate cellular motile functions through the control of dynamic actin polymerization. The status of cytoplasmic actin is sensed and communicated to the nucleus in order to elicit required changes in gene expression.
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The status of cytoskeletal actin dynamics is communicated to the nucleus by the shuttling of globular actin (G-actin)- and filamentous actin (F-actin)-binding proteins (G-ABPs and F-ABPs, respectively). Cytoskeletal F-actin complexes are often associated with additional proteins (F-ACAPs), which can also translocate to the nucleus.
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Myocardin-related transcription factors (MRTFs) are cofactors of the transcription factor serum response factor (SRF). MRTFs bind cytoplasmic G-actin and are released to translocate to the nucleus on stimulation of actin polymerization.
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The nuclear activity of MRTFs is subject to regulation by nuclear G-actin. G-actin regulates activity of the MRTF–SRF complex and the nuclear export of MRTF.
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The actin–MRTF–SRF circuit controls the expression of target genes that encode structural and regulatory components of the actin cytoskeleton. Thereby, positive and negative feedback loops can be activated to control cell motility by regulating actin dynamics.
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In addition to regulating the expression of cytoskeletal genes, SRF and members of the myocardin family regulate the expression of microRNAs, which provide additional feedback loops to modulate SRF signalling, cytoskeletal function and muscle development.
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Abnormalities in actin signalling mediated by the MRTF–SRF circuit are thought to have a key role in various diseases, including cancer, heart disease and vascular disorders.
Abstract
Numerous physiological and pathological stimuli promote the rearrangement of the actin cytoskeleton, thereby modulating cellular motile functions. Although it seems intuitively obvious that cell motility requires coordinated protein biosynthesis, until recently the linkage between cytoskeletal actin dynamics and correlated gene activities remained unknown. This knowledge gap was filled in part by the discovery that globular actin polymerization liberates myocardin-related transcription factor (MRTF) cofactors, thereby inducing the nuclear transcription factor serum response factor (SRF) to modulate the expression of genes encoding structural and regulatory effectors of actin dynamics. This insight stimulated research to better understand the actin–MRTF–SRF circuit and to identify alternative mechanisms that link cytoskeletal dynamics and genome activity.
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Acknowledgements
We apologize to all colleagues whose work could not be cited in full owing to space restrictions. We thank G. Posern and B. Knöll for comments on the manuscript. E.N.O. was supported by grants from the National Institutes of Health, the American Heart Association, the Robert A. Welch Foundation and the Leducq Foundation. A.N. acknowledges financial support by the DFG (No120/12-3 and SFB 773/A3).
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Glossary
- F-actin
-
A flexible, helical polymer of G-actin monomers that is 5–9 nm in diameter. An F-actin polymer is polar, displaying a plus (+) and a minus (−) end.
- Focal adhesion
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A cellular structure that links the ECM on the outside of the cell to the actin cytoskeleton inside the cell through integrin receptors.
- Guanine nucleotide exchange factor
-
A protein that activates a specific small GTPase by catalysing the exchange of bound GDP for GTP.
- Heterotrimeric G protein
-
One of a family of heterotrimeric cytoplasmic signal mediators composed of an -subunit containing a GTP-binding site and intrinsic GTPase activity, together with a hydrophobic and an often acylated β- and γ-protein subcomplex. The β- and γ-protein subcomplex may be activated by the dissociation of α–GTP, which is initiated by GTP exchange on the α-subunit.
- Epithelial–mesenchymal transition
-
The transformation of an epithelial cell into a mesenchymal cell with migratory and invasive properties.
- Adherens junction
-
A cell–cell adhesion complex that contains classical cadherins and catenins that are attached to cytoplasmic actin filaments.
- SAP domain
-
(SAFA or SAFB, acinus and PIAS domain). A peptide motif found in several proteins known to contact DNA.
- Leu zipper
-
A Leu-rich domain in a protein that binds to other proteins with a similar domain.
- LIM domain
-
(Lin11, Isl1 and Mec3 domain). A zinc-binding protein domain that ligates two zinc ions. LIM domains mediate interactions with other proteins and have diverse functions as regulators of gene expression, cell adhesion and motility, and signal transduction.
- RPEL domain
-
A protein domain containing the amino acid sequence Arg-Pro-X-X-X-Glu-Leu that is found triplicated in the myocardin family of transcriptional coactivators. RPEL domains form stable complexes with G-actin.
- Barbed end
-
The plus (+) end of the polar F-actin polymer that, in contrast to the minus (−) end, is more active with regard to incorporation of G-actin into the polymer (polymer elongation).
- Leiomyosarcoma
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A rare type of cancer (a soft tissue sarcoma) that is a malignant neoplasm of smooth muscle origin.
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Olson, E., Nordheim, A. Linking actin dynamics and gene transcription to drive cellular motile functions. Nat Rev Mol Cell Biol 11, 353–365 (2010). https://doi.org/10.1038/nrm2890
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DOI: https://doi.org/10.1038/nrm2890
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