RASSF1A Is Part of a Complex Similar to the Drosophila Hippo/Salvador/Lats Tumor-Suppressor Network

Division of Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
Current Biology (Impact Factor: 9.92). 05/2007; 17(8):700-5. DOI: 10.1016/j.cub.2007.02.055
Source: PubMed

ABSTRACT The Ras Association Domain Family 1A (RASSF1A) gene is one of the most frequently silenced genes in human cancer. RASSF1A has been shown to interact with the proapoptotic kinase MST1. Recent work in Drosophila has led to the discovery of a new tumor-suppressor pathway involving the Drosophila MST1 and MST2 ortholog, Hippo, as well as the Lats/Warts serine/threonine kinase and a protein named Salvador (Sav). Little is known about this pathway in mammalian cells. We report that complexes consisting of RASSF1A, MST2, WW45 (the human ortholog of Sav), and LATS1 exist in human cells. MST2 enhances the RASSF1A-WW45 interaction, which requires the C-terminal SARAH domain of both proteins. Components of this complex are localized at centrosomes and spindle poles from interphase to telophase and at the midbody during cytokinesis. Both RASSF1A and WW45 activate MST2 by promoting MST2 autophosphorylation and LATS1 phosphorylation. Mitosis is delayed in Rassf1a(-/-) mouse embryo fibroblasts and frequently results in cytokinesis failure, similar to what has been observed for LATS1-deficient cells. RASSF1A, MST2, or WW45 can rescue this defect. The complex of RASSF1A, MST2, WW45, and LATS1 consists of several tumor suppressors, is conserved in mammalian cells, and appears to be involved in controlling mitotic exit.

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Available from: Gerd Pfeifer, Dec 19, 2014
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    • "Previous studies have included Rassf1a knockout mouse models, overexpression of RASSF1A or silencing its expression using RNAi in cancer cell lines. The outcome of these studies are in agreement that the functions of RASSF1A include tumour growth inhibition through the promotion of different apoptotic pathways, microtubule stabilisation, subsequent regulation of the cell cycle and cell migration (Avruch et al., 2006; Dallol et al., 2005; Donninger et al., 2011; Guo et al., 2007; Matallanas et al., 2007; Oh et al., 2006; Praskova et al., 2004). The apoptotic pathways regulated by RASSF1 include KRas and death receptor-induced apoptosis, and the Hippo pathway through its SARAH domainmediated interaction with MST1 and MST2, whilst it regulates the cell cycle at metaphase, G1, G2/M and prometaphase. "
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    ABSTRACT: Not all proteins implicated in direct binding to Ras appear to have a positive role in the generation and progression of tumours; examples include Phospholipase C epsilon (PLCɛ) and some members of the Ras-association domain family (RASSF). The RASSF family comprises of ten members, known as RASSF1 to RASSF10. PLCɛ and RASSF members carry a common Ras-association domain (RA) that can potentially bind Ras oncoproteins and mediate Ras-regulated functions. RASSF1 to RASSF6 also share a common SARAH domain that facilitates protein-protein interactions with other SARAH domain proteins. The majority of the family are frequently downregulated by epigenetic silencing in cancers. They are implicated in various important biological processes including apoptosis, microtubule stabilisation and cell cycle regulation. Recent studies have reinforced the tumour suppressive properties of the RASSF family, with new evidence of emerging pathways and novel functions that suggest a wider role for these proteins. This review will first describe an emerging role of PLCɛ in tumour suppression and then focus on and summarise the new findings on the RASSF family in the last five years to consolidate their well-established functions, and highlight the new regulatory roles of specific RASSF members.
    08/2013; DOI:10.1016/j.jbior.2013.07.008
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    • "RASSF1A can form complexes with MST1/2 and WW45 through conserved SARAH domains [71] [82] [83] [111], which seems to play a role in Hippo dependent and independent apoptotic signalling [112]. Significantly, RASSF1A null cells display cytokinesis failure [82], which is a similar phenotype as observed in LATS2 null cells [92] [93]. Furthermore, it has been reported that RASSF1A overexpression induces a G2/M cell cycle arrest [113], most likely by RASSF1A regulating APC-Cdc20 E3 ligase activity which affects mitotic progression [114]. "
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    ABSTRACT: Over the past decade Hippo kinase signalling has been established as an essential tumour suppressor pathway controlling tissue growth in flies and mammals. All members of the Hippo core signalling cassette are conserved from yeast to humans, whereby the yeast analogues of Hippo, Mats and Lats are central components of the mitotic exit network and septation initiation network in budding and fission yeast, respectively. Here, we discuss how far core Hippo signalling components in Drosophila melanogaster and mammals have reported similar mitotic functions as already established for their highly conserved yeast counterparts.
    Seminars in Cell and Developmental Biology 04/2012; 23(7):794-802. DOI:10.1016/j.semcdb.2012.04.001 · 5.97 Impact Factor
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    • "For example, cyclin E, diap1 and bantam are key genes downstream of Yki in Drosophila (Zhao et al., 2010), but have not been shown to be transcriptional targets of its orthologs (Ota and Sasaki, 2008; Zhao et al., 2008; Lai et al., 2011). Additionally, whereas dRASSF antagonizes the Hippo pathway in Drosophila (Polesello et al., 2006), its mammalian homolog RASSF1A activates MST1/2 and the kinase cascade (Guo et al., 2007). Also upstream, Drosophila Kibra interacts with multiple Hippo pathway components including mer, ex, hpo and dlats. "
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    ABSTRACT: The Hippo signaling network is proving to be an essential regulator within the cell, participating in multiple cellular phenotypes including cell proliferation, apoptosis, cell migration and organ size control. Much of this pathway is conserved from flies to mammals; however, how the upstream components, namely Expanded, affect downstream processes in mammalian systems has remained elusive. Only recently has human Expanded (hEx), also known as FRMD6 or Willin, been identified. However, its functional significance with respect to its putative tumor suppressor function and activation of the Hippo pathway has not been studied. In this study, we show for the first time that hEx possesses several tumor suppressor properties. First, hEx dramatically inhibits cell proliferation in two human cancer cell lines, MDA-MB-231 and MDA-MB-436 cells, and sensitizes these cells to the chemotherapeutic drug Taxol. Furthermore, downregulation of hEx in the immortalized MCF10A breast cell line leads to enhanced proliferation and resistance to Taxol treatment. As evidence for its tumor suppressor function, overexpression of hEx inhibits colony formation, soft agar colony growth in vitro and in vivo tumor growth in nude mice. Although Drosophila expanded (ex) can activate the Hippo pathway, surprisingly no significant alterations were discovered in the phosphorylation status of any of the Hippo pathway components, including downstream tumor suppressor LATS1, upon overexpression of hEx. In addition, knockdown of both LATS1 and LATS2 in hEx-overexpressing cells was unable to rescue the hEx phenotype, suggesting that hEx functions independently of the Hippo pathway in this cell line. Alternatively, we propose a mechanism through which hEx inhibits progression through the S phase of the cell cycle by upregulating p21(Cip1) and downregulating Cyclin A. This is the first study to functionally characterize hEx and show that hEx acts in a distinct manner compared with Drosophila expanded.
    Oncogene 07/2011; 31(9):1189-95. DOI:10.1038/onc.2011.318 · 8.56 Impact Factor
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