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

Jiang, Lingyan; Rong, Rong; Sheikh, M. Saeed; Huang, Ying

doi:10.1074/jbc.m110.186494

Cited by 35 publications

(32 citation statements)

References 38 publications

(60 reference statements)

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“…Although RASSF1A protein levels have been proposed to fluctuate during the cell cycle (Jiang et al, 2011;Song et al, 2008), a clear connection with a physiological signal that modulates RASSF1A protein (A) Co-IP of YAP1 with SMAD2 or p73 in response to increasing concentrations of doxycycline (DOX) and TGF-b1 treatment for 2 hr. (B) Nuclear SMAD2 in U2OS TetON-RASSF1A upon treatment with doxycycline (1 mg/ml) and stimulation with TGF-b1 for 2 hr.…”

Section: Discussionmentioning

confidence: 99%

“…Background ubiquitination could be partially attributed to endogenous paracrine TGF-b signaling ( Figure S1D) and TGF-b-independent RASSF1A ubiquitination (Jiang et al, 2011;Song et al, 2008). We next utilized NBE-1 (normal bronchial epithelial cells) and MCF10A (mammary epithelial cells) to assess RASSF1A levels after treatment with TGF-b in primary cell lines.…”

Section: Rassf1a Is Degraded In Response To Tgf-b Signalingmentioning

confidence: 99%

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TGF-β Targets the Hippo Pathway Scaffold RASSF1A to Facilitate YAP/SMAD2 Nuclear Translocation

et al. 2016

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Epigenetic inactivation of the Hippo pathway scaffold RASSF1A is associated with poor prognosis in a wide range of sporadic human cancers. Loss of expression reduces tumor suppressor activity and promotes genomic instability, but how this pleiotropic biomarker is regulated at the protein level is unknown. Here we show that TGF-β is the physiological signal that stimulates RASSF1A degradation by the ubiquitin-proteasome pathway. In response to TGF-β, RASSF1A is recruited to TGF-β receptor I and targeted for degradation by the co-recruited E3 ubiquitin ligase ITCH. RASSF1A degradation is necessary to permit Hippo pathway effector YAP1 association with SMADs and subsequent nuclear translocation of receptor-activated SMAD2. We find that RASSF1A expression regulates TGF-β-induced YAP1/SMAD2 interaction and leads to SMAD2 cytoplasmic retention and inefficient transcription of TGF-β targets genes. Moreover, RASSF1A limits TGF-β induced invasion, offering a new framework on how RASSF1A affects YAP1 transcriptional output and elicits its tumor-suppressive function.

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Section: Discussionmentioning

confidence: 99%

Section: Rassf1a Is Degraded In Response To Tgf-b Signalingmentioning

confidence: 99%

TGF-β Targets the Hippo Pathway Scaffold RASSF1A to Facilitate YAP/SMAD2 Nuclear Translocation

et al. 2016

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“…Interestingly, RASSF1A has to be phosphorylated on Ser202 by cyclin D-cyclin-dependent kinase 4 to be able to interact with Skp2 [166]. In mitosis, Cullin 4A (CULL4A) promotes RASSF1A degradation [172]. In this case DNA damage-binding protein 1 directly interacts with RASSF1A and brings it to the CUL4A E3 ligase complex during mitosis.…”

Section: Post-translational Modifications Of Rassf1amentioning

confidence: 99%

RASSF tumor suppressor gene family: Biological functions and regulation

et al. 2014

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a b s t r a c tGenetic changes through allelic loss and nucleic acid or protein modifications are the main contributors to loss of function of tumor suppressor proteins. In particular, epigenetic silencing of genes by promoter hypermethylation is associated with increased tumor severity and poor survival. The RASSF (Ras association domain family) family of proteins consists of 10 members, many of which are tumor suppressor proteins that undergo loss of expression through promoter methylation in numerous types of cancers such as leukemia, melanoma, breast, prostate, neck, lung, brain, colorectal and kidney cancers. In addition to their tumor suppressor function, RASSF proteins act as scaffolding agents in microtubule stability, regulate mitotic cell division, modulate apoptosis, control cell migration and cell adhesion, and modulate NFjB activity and the duration of inflammation. The ubiquitous functions of these proteins highlight their importance in numerous physiological pathways. In this review, we will focus on the biological roles of the RASSF family members and their regulation.

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“…Immunoprecipitation and S-tag protein pull assays were performed as we have previously described (33).…”

Section: Immunoprecipitation and S-tag Protein Pull Downmentioning

confidence: 99%

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

Cited by 35 publications

References 38 publications

TGF-β Targets the Hippo Pathway Scaffold RASSF1A to Facilitate YAP/SMAD2 Nuclear Translocation

TGF-β Targets the Hippo Pathway Scaffold RASSF1A to Facilitate YAP/SMAD2 Nuclear Translocation

RASSF tumor suppressor gene family: Biological functions and regulation

Mitotic Arrest by Tumor Suppressor RASSF1A Is Regulated via CHK1 Phosphorylation

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