Linking actin dynamics and gene transcription to drive cellular motile functions

Abstract

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.