Aurora B–Mediated Phosphorylation of RASSF1A Maintains Proper Cytokinesis by Recruiting Syntaxin16 to the Midzone and Midbody

Song, Su Jung; Kim, Soon Jung; Song, Min Sup; Lim, Dae–Sik

doi:10.1158/0008-5472.can-09-1554

Cited by 35 publications

(45 citation statements)

References 15 publications

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“…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]. In addition, it was found that Aurora A regulates RASSF1A during prometaphase progression [115,116], while Aurora B phosphorylation of RASSF1A plays a role in the regulation of cytokinesis [117]. These reports strongly suggest that RASSF1A has diverse roles in mitosis.…”

Section: Mammalian Hippo Signalling In the G2/m Phase Of The Cell Cyclementioning

confidence: 92%

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

Hergovich

Hemmings

2012

Seminars in Cell & Developmental Biology

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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.

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Section: Mammalian Hippo Signalling In the G2/m Phase Of The Cell Cyclementioning

confidence: 92%

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

Hergovich

Hemmings

2012

Seminars in Cell & Developmental Biology

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“…Recently, we identified the first kinase, the mitotic kinase Aurora-A, for RASSF1A; Aurora-A phosphorylates and modulates the ability of RASSF1A to associate with microtubule during mitosis (17). Since then, a number of RASSF1A kinases have also been identified, including cyclin-dependent kinase-4 (18), PKC (19), MST1 (macrophage stimulating-1) (20), and Aurora-B (21), which have diverse effects on RASSF1A function. Clearly, more studies are needed to further investigate the regulation of this important tumor suppressor protein.…”

mentioning

confidence: 99%

Cullin-4A·DNA Damage-binding Protein 1 E3 Ligase Complex Targets Tumor Suppressor RASSF1A for Degradation during Mitosis

Jiang

Rong

Sheikh

et al. 2011

Journal of Biological Chemistry

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Tumor suppressor RASSF1A (RAS association domain family 1, isoform A) is known to play an important role in regulation of mitosis; however, little is known about how RASSF1A is regulated during the mitotic phase of the cell cycle. In the present study, we have identified Cullin-4A (CUL4A) as a novel E3 ligase for RASSF1A. Our results demonstrate that DNA damage-binding protein 1 (DDB1) functions as a substrate adaptor that directly interacts with RASSF1A and bridges RASSF1A to the CUL4A E3 ligase complex. Depletion of DDB1 also diminishes intracellular interactions between RASSF1A and CUL4A. Our results also show that RASSF1A interacts with DDB1 via a region containing amino acids 165-200, and deletion of this region abolishes RASSF1A and DDB1 interactions. We have found that CUL4A depletion results in increased levels of RASSF1A protein due to increased half-life; whereas overexpression of CUL4A and DDB1 markedly enhances RASSF1A protein ubiquitination resulting in reduced RASSF1A levels. We further show that CUL4A-mediated RASSF1A degradation occurs during mitosis, and depletion of CUL4A markedly reverses mitotic-phase-stimulated RASSF1A degradation. We also note that overexpression of CUL4A antagonizes the ability of RASSF1A to induce M-phase cell cycle arrest. Thus, our present study demonstrates that the CUL4A⅐DDB1 E3 complex is important for regulation of RASSF1A during mitosis, and it may contribute to inactivation of RASSF1A and promoting cell cycle progression.RASSF1A is a recently identified important tumor suppressor (1, 2). It is the major transcript of the seven alternatively spliced variants of the RASSF1 gene, including isoforms A-G (1, 2). Loss or altered expression of RASSF1A by either homozygous or heterozygous deletions of the RASSF1 gene (1) or by hypermethylation of the RASSF1 gene promoter (2-7) has been associated with the pathogenesis of a variety of malignancies. Restoration of RASSF1A expression has been shown to suppress tumorigenic growth, both in vitro and in vivo (2, 3, 8 -10). Although the in-depth molecular mechanisms by which RASSF1A functions as a tumor suppressor remain to be elucidated, recent evidence indicates that cell cycle regulation is an important aspect of its function. A number of recent studies including ours have shown that RASSF1A induces cell cycle arrest in both G 1 /S-and mitotic (M)-phases (8,(11)(12)(13)(14)(15)(16). A number of mechanisms have been identified for its action on cell cycle control, for example, RASSF1A-mediated G 1 /S cell cycle arrest has been associated with the inhibition of cyclin D1 accumulating in the nucleus (15) and M-phase of cell cycle regulation is linked to the ability of RASSF1A to modulate the activity of anaphase-promoting complex (16) and microtubule dynamics (8,(11)(12)(13)(14).Despite a decade-long investigation establishing RASSF1A as an important tumor suppressor that plays a crucial role in cell growth control and apoptosis, little is known about its regulation at the protein level. Recently, we identified the first kinase,...

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“…Remarkably, a number of known RASSF1A kinases identified thus far all phosphorylate RASSF1A residues within this region. For example, Aurora-A and MST1 phosphorylate residues Threonine 202 and Serine 203 (16,19), Aurora-B and CDK4 phosphorylate Serine 203 (17,20), and PKC phosphorylates residue Serine 203 and Serine 197 (18). These phosphorylation sites of RASSF1A by various kinases seem to be clustered within a relatively small region (amino acids 184-203) of the RASSF1A protein.…”

Section: Discussionmentioning

confidence: 99%

“…The exogenous Flag-tagged CHK1 kinase was immunoprecipitated from 1.5 mg of total cell lysates by 5 mg of anti-Flag antibodies. The immunocomplex or alternatively 100 ng of active CHK1 kinase was then incubated together with 1 mg of purified RASSF1A in 50 mL of CHK1 kinase cocktail [20 …”

Section: In Vitro Kinase Assaymentioning

confidence: 99%

“…18), macrophage stimulating-1 (MST1; ref. 19), and Aurora-B (20) have also been identified to phosphorylate RASSF1A. Each of these kinases seems to regulate different aspects of RASSF1A function, suggesting that regulation of RASSF1A is a multiplex event involving multiple kinases that modulate RASSF1A function needed for various cellular processes.…”

Section: Introductionmentioning

confidence: 99%

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Mitotic Arrest by Tumor Suppressor RASSF1A Is Regulated via CHK1 Phosphorylation

Jiang

Rong

Sheikh

et al. 2014

Molecular Cancer Research

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The tumor suppressor RAS-association domain family 1 isoform A (RASSF1A) is known to play an important role in cell-cycle regulation. However, the molecular details about RASSF1A protein regulation are unclear. In this report, checkpoint kinase 1 (CHK1) is identified as a novel RASSF1A kinase that phosphorylates RASSF1A in vitro and under cellular conditions. Using tandem mass spectrometry and biochemical analysis, it was determined that CHK1 phosphorylates RASSF1A on Serine 184, which has been shown to be mutated in a subset of human primary nasopharyngeal carcinomas. Furthermore, Serine 184 phosphorylation of RASSF1A was significantly diminished by a CHK1-specific kinase inhibitor. Similarly, a kinase-dead CHK1 mutant was unable to phosphorylate Serine 184 whereas constitutively active-CHK1 enhanced phosphorylation. Molecular substitution of Serine 184 with aspartic acid, mimicking phosphorylation, abolished the ability of RASSF1A to interact with microtubules and induce M-phase arrest. Combined, these data indicate that phosphorylation of RASSF1A by CHK1 is important for mitotic regulation and provide valuable new insight into the regulatory mechanisms of RASSF1A function.Implications: This study reveals that CHK1-mediated phosphorylation of RASSF1A, at Serine 184, plays an important role in cell-cycle regulation and highlights that mutation of this CHK1 phosphorylation site in nasopharyngeal carcinoma has disease relevance.

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Aurora B–Mediated Phosphorylation of RASSF1A Maintains Proper Cytokinesis by Recruiting Syntaxin16 to the Midzone and Midbody

Cited by 35 publications

References 15 publications

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

Cullin-4A·DNA Damage-binding Protein 1 E3 Ligase Complex Targets Tumor Suppressor RASSF1A for Degradation during Mitosis

Mitotic Arrest by Tumor Suppressor RASSF1A Is Regulated via CHK1 Phosphorylation

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