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: 9.57). 05/2007; 17(8):700-5. DOI: 10.1016/j.cub.2007.02.055
Source: PubMed


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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    • "Active MST1/2 in complex with SAV1 phosphorylates LATS1/2, which in turn stimulates LATS‐MOB complex formation and activation of LATS kinase activity. Active LATS1/2 kinases phosphorylate and inactivate YAP1 and TAZ through 14‐3‐3 protein‐mediated cytoplasmic sequestration (Dong et al, 2007; Guo et al, 2007; Zhao et al, 2007; Lei et al, 2008; Oka et al, 2008; Zhang et al, 2008). When the Hpo pathway is inactive, hypo‐phosphorylated nuclear YAP1 and TAZ bind to the TEA domain transcription factors (TEAD1/2/3/4) to drive expression of pro‐growth and anti‐apoptotic genes (Wu et al, 2008; Zhao et al, 2008). "
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    ABSTRACT: Tissue homeostasis is controlled by signaling systems that coordinate cell proliferation, cell growth and cell shape upon changes in the cellular environment. Deregulation of these processes is associated with human cancer and can occur at multiple levels of the underlying signaling systems. To gain an integrated view on signaling modules controlling tissue growth, we analyzed the interaction proteome of the human Hippo pathway, an established growth regulatory signaling system. The resulting high-resolution network model of 480 protein-protein interactions among 270 network components suggests participation of Hippo pathway components in three distinct modules that all converge on the transcriptional co-activator YAP1. One of the modules corresponds to the canonical Hippo kinase cassette whereas the other two both contain Hippo components in complexes with cell polarity proteins. Quantitative proteomic data suggests that complex formation with cell polarity proteins is dynamic and depends on the integrity of cell-cell contacts. Collectively, our systematic analysis greatly enhances our insights into the biochemical landscape underlying human Hippo signaling and emphasizes multifaceted roles of cell polarity complexes in Hippo-mediated tissue growth control.
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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.
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    • "In addition, protein-protein interactions have also been shown to play critical roles in the regulation of Mst1 activity. Thus far, several proteins including Ras association domain family protein (Rassf) [16]–[18], hWW45 [17], [19], PHLPP1 [20], and Heat Shock Protein 70 (Hsp70) [21], have been identified to interact with Mst1 and regulate Mst1 activation. For instance, RASSF family of tumor suppressors have been shown to interact with and stabilize Mst1, thereby preventing Mst1 for the degradation and inhibiting tumor growth [18], [22]. "
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    ABSTRACT: Mammalian sterile 20-like kinase 1 (Mst1) is a critical component of the Hippo signaling pathway, which regulates a variety of biological processes ranging from cell contact inhibition, organ size control, apoptosis and tumor suppression in mammals. Mst1 plays essential roles in the heart disease since its activation causes cardiomyocyte apoptosis and dilated cardiomyopathy. However, the mechanism underlying Mst1 activation in the heart remains unknown. In a yeast two-hybrid screen of a human heart cDNA library with Mst1 as bait, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was identified as an Mst1-interacting protein. The interaction of GAPDH with Mst1 was confirmed by co-immunoprecipitation in both co-transfected HEK293 cells and mouse heart homogenates, in which GAPDH interacted with the kinase domain of Mst1, whereas the C-terminal catalytic domain of GAPDH mediated its interaction with Mst1. Moreover, interaction of Mst1 with GAPDH caused a robust phosphorylation of GAPDH and markedly increased the Mst1 activity in cells. Chelerythrine, a potent inducer of apoptosis, substantially increased the nuclear translocation and interaction of GAPDH and Mst1 in cardiomyocytes. Overexpression of GAPDH significantly augmented the Mst1 mediated apoptosis, whereas knockdown of GAPDH markedly attenuated the Mst1 activation and cardiomyocyte apoptosis in response to either chelerythrine or hypoxia/reoxygenation. These findings reveal a novel function of GAPDH in Mst1 activation and cardiomyocyte apoptosis and suggest that disruption of GAPDH interaction with Mst1 may prevent apoptosis related heart diseases such as heart failure and ischemic heart disease.
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