Linking actin dynamics and gene transcription to drive cellular motile functions

• Published in: Nature reviews. Molecular cell biology Vol. 11; no. 5; pp. 353 - 365
• Main Authors: Nordheim, Alfred, Olson, Eric N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2010; Nature Publishing Group
• Subjects: 631/337/572; 631/57/343/1361; 631/80/128/1276; 631/80/86; Abnormalities; Actin; Actins - metabolism; Animals; Biochemistry; Biomedical and Life Sciences; Biosynthesis; Cancer Research; Cardiovascular diseases; Cell Biology; Cell Movement; Cell surface; Circuits; Cofactors; Control theory; Coronary artery disease; Cytoskeleton; Developmental Biology; Dynamics; Feedback; Feedback loops; Gene expression; Genes; Genomes; Heart diseases; Humans; Kinases; Life Sciences; MicroRNAs; miRNA; Motility; Muscles; Negative feedback; Nuclear transport; Nuclei (cytology); Physiology; Polymerization; Proteins; review-article; Serum response factor; Serum Response Factor - metabolism; Signal Transduction; Signaling; Stem Cells; Trans-Activators - metabolism; Transcription factors; Transcription, Genetic
• ISSN: 1471-0072; 1471-0080
• DOI: 10.1038/nrm2890

Key Points 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. 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. 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. 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. 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. 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. 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. The link between cytoskeletal actin dynamics and correlated gene activities was unclear. However, the discovery that globular actin polymerization liberates myocardin family transcriptional cofactors to induce serum response factor, which modulates the expression of genes encoding effectors of actin dynamics, has helped bridge this gap in our knowledge. 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.