Abstract
Nuclear actin participates in many essential cellular processes including gene transcription, chromatin remodelling and mRNA processing. Actin shuttles into and out the nucleus through the action of dedicated transport receptors importin‐9 and exportin‐6, but how this transport is regulated remains unclear. Here, we show that RASSF1A is a novel regulator of actin nucleocytoplasmic trafficking and is required for the active maintenance of nuclear actin levels through supporting binding of exportin‐6 (XPO6) to RAN GTPase. RASSF1A (Ras association domain family 1 isoform A) is a tumour suppressor gene frequently silenced by promoter hypermethylation in all major solid cancers. Specifically, we demonstrate that endogenous RASSF1A localises to the nuclear envelope (NE) and is required for nucleocytoplasmic actin transport and the concomitant regulation of myocardin‐related transcription factor A (MRTF‐A), a co‐activator of the transcription factor serum response factor (SRF). The RASSF1A/RAN/XPO6/nuclear actin pathway is aberrant in cancer cells where RASSF1A expression is lost and correlates with reduced MRTF‐A/SRF activity leading to cell adhesion defects. Taken together, we have identified a previously unknown mechanism by which the nuclear actin pool is regulated and uncovered a previously unknown link of RASSF1A and MRTF‐A/SRF in tumour suppression.
Highlights
Actin is one of the most highly conserved cytoskeletal proteins and found in all eukaryotic cells
RASSF1A promoter methylation is widely appreciated to correlate with adverse prognosis, and we find a significant correlation between this epigenetic event and serum response factor (SRF) mRNA levels indicating that loss of nuclear actin regulation and myocardin-related transcription factor A (MRTF-A)/SRF is likely to contribute to clinical parameters (Fig 6A, top)
Nuclear actin is exported from the nucleus by XPO6, independently of the general export receptor CRM1, and it is imported by IPO9 (Stuven et al, 2003; Dopie et al, 2012)
Summary
Actin is one of the most highly conserved cytoskeletal proteins and found in all eukaryotic cells. Nuclear actin monomers have been shown to directly regulate the myocardin-related transcription factor A (MRTF-A), a mechanosensitive co-factor of the serum response factor (SRF) transcription pathway (Vartiainen et al, 2007; Baarlink et al, 2013). The Ras association domain family (RASSF) genes are upstream regulators of the Hippo tumour suppressor pathway. Gene deletion and germline mutations exist, the most widespread loss of RASSF1A function occurs through promoter hypermethylation-associated transcriptional silencing (Grawenda & O’Neill, 2015). RASSF1A directly binds Hippo kinases, mammalian sterile 20-like kinases 1 and 2 (MST1 and MST2) through the SARAH domain, promoting downstream Hippo pathway signalling to YAP1 (Guo et al, 2007; Matallanas et al, 2007).
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