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Review
. 2014:5:e27539.
doi: 10.4161/sgtp.27539. Epub 2014 Mar 6.

Rho, nuclear actin, and actin-binding proteins in the regulation of transcription and gene expression

Eeva Kaisa Rajakylä  1 , Maria K Vartiainen  1
Affiliations
Review

Rho, nuclear actin, and actin-binding proteins in the regulation of transcription and gene expression

Eeva Kaisa Rajakylä et al. Small GTPases. 2014.

Abstract

Actin cytoskeleton is one of the main targets of Rho GTPases, which act as molecular switches on many signaling pathways. During the past decade, actin has emerged as an important regulator of gene expression. Nuclear actin plays a key role in transcription, chromatin remodeling, and pre-mRNA processing. In addition, the "status" of the actin cytoskeleton is used as a signaling intermediate by at least the MKL1-SRF and Hippo-pathways, which culminate in the transcriptional regulation of cytoskeletal and growth-promoting genes, respectively. Rho GTPases may therefore regulate gene expression by controlling either cytoplasmic or nuclear actin dynamics. Although the regulation of nuclear actin polymerization is still poorly understood, many actin-binding proteins, which are downstream effectors of Rho, are found in the nuclear compartment. In this review, we discuss the possible mechanisms and key proteins that may mediate the transcriptional regulation by Rho GTPases through actin.

Keywords: Hippo; MKL1; Rho GTPase; SRF; actin; nucleus.

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Figures

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Figure 1. ABPs in the nucleus. Many ABPs that are downstream targets of Rho GTPases are also present in the cell nucleus, where they have been linked to gene expression processes and can regulate nuclear actin dynamics. Two alternatives exist on how Rho GTPases can regulate nuclear ABPs. (1) Rho GTPases can activate ABPs in the cytoplasm and the activated ABPs (ABP*) then shuttle into the nucleus. (2) Upstream signaling could activate the nuclear localized Rho GTPases, which then signals to ABPs in the nucleus. Nuclear ABPs may influence gene expression by regulating nuclear actin dynamics (upper part of the figure). Importin-9 (Ipo9) together with ADF/cofilin (cof) mediates the nuclear import of actin (a). Exportin-6 (Exp6) together with profilin mediates the nuclear export of actin (b). Profilin and mDia formins promote actin polymerization by mediating the addition of ATP-actin monomers to the growing end (+ end) of the actin filament (c). In the filament, ATP is hydrolyzed to ADP and ADP-actin monomers are then released from the minus end (- end). ADF/cofilins (cof) mediate the disassembly of actin filaments (d). Arp2/3 complex and its activators WASp/N-WASp and WAVEs may contribute to nuclear actin nucleation (e). Several ABPs themselves have also been linked to gene expression processes, and also actin (red arrow head) is a component of many nuclear complexes (lower part of the figure). Arp2/3 complex, WASp/N-WASp, WAVEs, cofilin-1 (cof), Nuclear myosin I (NMI), Myosin VI (MyoVI), Myosin Vb (MyoVb) and filamin (Fln) have been linked to RNA polymerase function (pol) (f). In this context N-WASp can associate with PSF-NonO complex that binds the polymerase. NMI also participates to chromatin remodeling together with actin (g). Profilin, as well as Myosin Va (MyoVa) are both linked to pre-mRNA splicing. hnRNPs are also involved at this level together with actin (h).
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Figure 2. Rho GTPases as regulators of gene-specific transcription factors. Different plasma membrane receptors (a) and mechanical signals mediated by either cell-extracellular matrix adhesions (b) or cell-cell contacts (c) regulate Rho GTPase activity, which promotes actin polymerization (d). These same signals also act upstream of the Hippo-pathway (e), where activation of Mst1/2 and Lats1/2 kinases exclude YAP/TAZ from the nucleus, and prevent it from activating TEAD-mediated transcription. MKL1 is a sensor for actin monomer levels, and actin-binding inhibits nuclear import of MKL1 (f), and enhances its nuclear export (g). Upon actin polymerization, the actin monomer levels decrease and actin-free MKL1 can enter the nucleus (h). In the nucleus, actin-free MKL1 can activate SRF-mediated transcription (i). Actin filaments (or their subpopulation) also regulate the Hippo-pathway, and the regulation can occur either through a Lats-dependent mechanism (j) or directly at YAP/TAZ (k), via an unknown mechanism. Membrane molecules may therefore influence YAP/TAZ activity directly through the regulation of Hippo pathway or through Rho GTPase-dependent actin regulation. The contribution of nuclear actin in YAP/TAZ regulation has not been studied, as indicated by a question mark.
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