The SARAH Domain of RASSF1A and Its Tumor Suppressor Function

Dittfeld, Claudia; Richter, Antje; Steinmann, Katrin; Klagge-Ulonska, Antje; Dammann, Reinhard

doi:10.1155/2012/196715

Cited by 30 publications

(27 citation statements)

References 52 publications

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“…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). Intriguingly, the RASSF1A/ RAN/XPO6 complex includes MST2, suggesting that the recruitment of RASSF1A to MST2 at the NE potentially supports XPO6 binding via the SARAH domain (Dittfeld et al, 2012) and this is important for the active participation in actin-profilin nucleocytoplasmic shuttling. We found that lack of RASSF1A, a phenomenon commonly observed in human tumours, leads to accumulation of actin within the nucleus due to defective nuclear export.…”

Section: Discussionmentioning

confidence: 99%

RASSF 1A is required for the maintenance of nuclear actin levels

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 99%

RASSF 1A is required for the maintenance of nuclear actin levels

et al. 2019

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“…The process of signal transduction involves the formation of MST2 dimers, and the dimerization process is governed by the interaction through SARAH domains [12,19,[29][30][31][32] ( Figure 3A). In addition, RASSF scaffolds also interact with and regulate the activity of MST proteins through protein interactions mediated by their SARAH domain ( Figure 3B).…”

Section: Sarah Domainsmentioning

confidence: 99%

“…For example, interactions between RASSF1A (and RASSF1C) and MST1 and MST2 have been identified and analyzed showing that this interaction depends on the C-terminal SARAH domain, i.e. dimerization of both SARAH domains of each protein [31]. Nevertheless, few crystal structures are available for heterodimers, i.e.…”

Section: Sarah-sarah Domain Interactionsmentioning

confidence: 99%

MST2-RASSF protein–protein interactions through SARAH domains

Sánchez‐Sanz¹,

Matallanas²,

Nguyen³

et al. 2015

Brief Bioinform

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The detailed, atomistic-level understanding of molecular signaling along the tumor-suppressive Hippo signaling pathway that controls tissue homeostasis by balancing cell proliferation and death through apoptosis is a promising avenue for the discovery of novel anticancer drug targets. The activation of kinases such as Mammalian STE20-Like Protein Kinases 1 and 2 (MST1 and MST2)-modulated through both homo- and heterodimerization (e.g. interactions with Ras association domain family, RASSF, enzymes)-is a key upstream event in this pathway and remains poorly understood. On the other hand, RASSFs (such as RASSF1A or RASSF5) act as important apoptosis activators and tumor suppressors, although their exact regulatory roles are also unclear. We present recent molecular studies of signaling along the Ras-RASSF-MST pathway, which controls growth and apoptosis in eukaryotic cells, including a variety of modern molecular modeling and simulation techniques. Using recently available structural information, we discuss the complex regulatory scenario according to which RASSFs perform dual signaling functions, either preventing or promoting MST2 activation, and thus control cell apoptosis. Here, we focus on recent studies highlighting the special role being played by the specific interactions between the helical Salvador/RASSF/Hippo (SARAH) domains of MST2 and RASSF1a or RASSF5 enzymes. These studies are crucial for integrating atomistic-level mechanistic information about the structures and conformational dynamics of interacting proteins, with information available on their system-level functions in cellular signaling.

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“…Studies show that the RASSF1A gene rarely mutates, and its low or loss of expression is mainly due to hypermethylation of the CpG island in the promoter region 8 . RASSF1A can be used as a negative upstream regulator of YAP [9][10][11] , which may play an important role in psoriasis pathogenesis. However, its expression and mechanism in psoriasis are still unclear.…”

Section: Introductionmentioning

confidence: 99%

RASSF1A Regulates the Abnormal Cell Proliferation in Psoriasis via Inhibition of YAP

Jia

Wang

Zheng

et al. 2020

Preprint

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Background: Psoriasis is a chronic, inflammatory skin disease with high incidence, treatment resistance, and high recurrence. Currently, the exact etiology and pathogenesis are unclear. The goal of this study was to characterize the role of the upstream negative regulator RAS-association domain family 1A (RASSF1A) on Yes-associated protein (YAP) in psoriasis.Methods: Skin lesions of 22 psoriasis patients and 19 normal skin tissue controls were used. Human epidermal keratinocytes were stimulated with M5 (IL-1 α, IL-17, IL-22, TNF-α, oncostatin M), to establish the psoriatic cell model. Methylation inhibitor, 5-Aza-CdR was prepared at different concentrations (5, 10, 20 μmol/L). Cells were infected with lentivirus vector overexpressing RASSF1A. Twenty-five 6-8-week-old female BALB/c mice were used to establish the psoriatic mouse model. Mice were randomly divided into five groups: control (Vaseline applied daily), psoriasis (imiquimod applied daily), and the three different 5-Aza-CdR concentrations (applied daily with imiquimod). Methylation specific PCR (MSP) was used to detect RASSF1A methylation, and immunohistochemistry was used to detect RASSF1A expression in skin lesions. After adding 5-Aza-CdR or lentivirus vector overexpressing RASSF1A, YAP expression, cell proliferation, cell cycle, apoptosis, inflammatory cytokines and related signal pathway activity were detected.Results: As RASSF1A methylation level increased, its expression in psoriasis patients and mice with skin lesions decreased. Addition of 5-Aza-CdR or lentivirus vector overexpressing RASSF1A increased the expression of RASSF1A, reduced the expression of YAP and inflammatory cytokines, cell proliferation, as well as AKT, ERK, STAT3 and NF-κB signaling pathway activities, induced cell cycle arrest in G0/G1 phase, increased apoptosis, and improved skin lesions.Conclusions: RASSF1A inhibited the proliferation of psoriatic cells, induced apoptosis, and reduced the expression of inflammatory factors by inhibiting YAP expression. Based on our findings, targeted drugs that can inhibit RASSF1A methylation and increase its expression may be useful in the treatment of psoriasis.

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The SARAH Domain of RASSF1A and Its Tumor Suppressor Function

Cited by 30 publications

References 52 publications

RASSF 1A is required for the maintenance of nuclear actin levels

RASSF 1A is required for the maintenance of nuclear actin levels

MST2-RASSF protein–protein interactions through SARAH domains

RASSF1A Regulates the Abnormal Cell Proliferation in Psoriasis via Inhibition of YAP

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