Characterizing WW Domain Interactions of Tumor Suppressor WWOX Reveals Its Association with Multiprotein Networks

Abu-Odeh, Mohammad; Bar-Mag, Tomer; Huang, Haiming; Kim, TaeHyung; Salah, Zaidoun; Abdeen, Suhaib K.; Sudol, Marius; Reichmann, Dana; Sidhu, Sachdev S.; Kim, Philip M.; Aqeilan, Rami I.

doi:10.1074/jbc.m113.506790

Cited by 84 publications

(128 citation statements)

References 67 publications

Supporting

Mentioning

121

Contrasting

Order By: Relevance

“…We wanted to determine the strategy specific to WWOX's tandem WW domains. Our group applied a combination of proteomic analysis, GST pulldown, and immunoprecipitation experiments to demonstrate that the main interacting module of WWOX is its WW1 domain (41). These observations were supported by the work of the Farooq group (42, 43), demonstrating that the WW2 domain of WWOX shows very low affinity to PPXY partners.…”

Section: Expanded Search: the Many Faces Of Wwox Unraveled By Its Parsupporting

confidence: 52%

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Abu-Remaileh¹,

Joy-Dodson²,

Schueler‐Furman³

et al. 2015

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

WW domain-containing oxidoreductase (WWOX), originally marked as a likely tumor suppressor gene, has over the years become recognized for its role in a much wider range of cellular activities. Phenotypic effects displayed in animal studies, along with resolution of WWOX's architecture, fold, and binding partners, point to the protein's multifaceted biological functions. Results from a series of complementary experiments seem to indicate WWOX's involvement in metabolic regulation. More recently, clinical studies involving cases of severe encephalopathy suggest that WWOX also plays a part in controlling CNS development, further expanding our understanding of the breadth and complexity of WWOX behavior. Here we present a short overview of the various approaches taken to study this dynamic gene, emphasizing the most recent findings regarding WWOX's metabolic-and CNS-associated functions and their underlying molecular basis.The WWOX gene initially became a research target due to its localization in a region of considerable chromosomal instability (16q23.2), at common fragile site (CFS) 3 FRA16D, which immediately marked it as a possible tumor suppressor gene (TSG) (1, 2). Inactivation of TSGs at CFSs has long been known as a hallmark of cancer (3). CFSs are evolutionarily conserved genomic regions that are sensitive to replicative stress (4). In 2010, Beroukhim et al. (5) demonstrated that deletion of TSGs spanning CFSs is among the most significant driver events in cancer. Although highly recombinogenic, CFSs are rarely involved in oncogenic activation, suggesting that CFSs are mainly hot spots for inactivation of tumor suppressors (3). A number of animal studies were conducted on WWOX, and in keeping with the above paradigm, many insights were gained into WWOX's association with cancer development (reviewed elsewhere (6 -10)). However, a few surprising results led the research in other unanticipated directions, linking WWOX to regulation of metabolic function, as well as neuronal development (Fig. 1). These animal model studies were complemented by studies on the cellular and molecular levels, modeling WWOX structure and identifying its potential binding partners, thus generating a comprehensive functional model of WWOX activity.This review sketches out how our view of WWOX has evolved over the years, with emphasis on the recent findings that link WWOX to metabolic regulation and CNS homeostasis. We begin with an overview of the original WWOX animal model studies, followed by an outline of subsequent WWOX research performed at the cellular and molecular levels. We review potential WWOX binding partners and their associated cellular pathways. We further define WWOX structure and architecture, expounding its behavior in the context of its two tandem WW domains and expansive short-chain dehydrogenase/reductase (SDR) region. Taken together, we generate a functional model of WWOX that highlights the versatility of this protein and suggests possible new directions for further study of WWOX's complex nature. Animal Model...

show abstract

Section: Expanded Search: the Many Faces Of Wwox Unraveled By Its Parsupporting

confidence: 52%

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Abu-Remaileh¹,

Joy-Dodson²,

Schueler‐Furman³

et al. 2015

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…32). Interestingly, using mass spectrometry and phage display experiments, Abu-Odeh and colleagues (33) identified very recently B-cell CLL/lymphoma 9 (BCL9), a homolog of BCL9-2, as a molecular partner of WWOX, validating our findings.…”

Section: Wwox Interacts With the B-catenin Coactivator Bcl9-2supporting

confidence: 73%

The Tumor-Suppressor WWOX and HDAC3 Inhibit the Transcriptional Activity of the β-Catenin Coactivator BCL9-2 in Breast Cancer Cells

El-Hage

Petitalot

Monsoro-Burq

et al. 2015

Molecular Cancer Research

View full text Add to dashboard Cite

The WW domain containing oxidoreductase (WWOX) has recently been shown to inhibit of the Wnt/b-catenin pathway by preventing the nuclear import of disheveled 2 (DVL2) in human breast cancer cells. Here, it is revealed that WWOX also interacts with the BCL9-2, a cofactor of the Wnt/b-catenin pathway, to enhance the activity of the b-catenin-TCF/LEF (T-cell factor/ lymphoid enhancer factors family) transcription factor complexes. By using both a luciferase assay in MCF-7 cells and a Xenopus secondary axis induction assay, it was demonstrated that WWOX inhibits the BCL9-2 function in Wnt/b-catenin signaling. WWOX does not affect the BCL9-2-b-catenin association and colocalizes with BCL9-2 and b-catenin in the nucleus of the MCF-7 cells. Moreover, WWOX inhibits the b-catenin-TCF1 interaction. Further examination found that HDAC3 associates with BCL9-2, enhances the inhibitory effect of WWOX on BCL9-2 transcriptional activity, and promotes the WWOX-BCL9-2 interaction, independent of its deacetylase activity. However, WWOX does not influence the HDAC3-BCL9-2 interaction. Altogether, these results strongly indicate that nuclear WWOX interacts with BCL9-2 associated with b-catenin only when BCL9-2 is in complex with HDAC3 and inhibits its transcriptional activity, in part, by inhibiting the b-catenin-TCF1 interaction. The promotion of the WWOX-BCL9-2 interaction by HDAC3, independent of its deacetylase activity, represents a new mechanism by which this HDAC inhibits transcription. Implications:The inhibition of the transcriptional activity of BCL9-2 by WWOX and HDAC3 constitutes a new molecular mechanism and provides new insight for a broad range of cancers.

show abstract

“…2C, lanes 7-12), suggesting blunted ATM function. In contrast, overexpression of WWOX but not WWOX-WFPA (a mutant form of WWOX, in which its WW1 domain has impaired interaction ability) (3,32) in a WWOXnegative breast cancer cell line, MDA-MB231, was associated with improved DDR signaling (Fig. S2A).…”

Section: Resultsmentioning

confidence: 95%

“…The WWOX protein contains two Nterminal WW domains mediating WWOX interaction with PP(proline)x(amino acid)Y(tyrosine)-containing proteins (11,17) and a central short-chain deyhdrogenase/reductase domain that has been proposed to function in steroidogenesis (18). Recent characterization of WWOX domains revealed that they interact, mainly through the WW1 domain, with multiprotein networks (3). The mechanism by which WWOX suppresses tumorigenicity is, however, not well-known.…”

mentioning

confidence: 99%

“…The DNA damage response (DDR) maintains the integrity of the genome in response to DNA damage. DDR is a complex signaling process that results in cell cycle arrest followed by either DNA repair or apoptosis if the DNA damage is too extensive to be repaired (1)(2)(3). Key mammalian damage response sensors are ataxia telangiectasia-mutated (ATM), ATM and Rad3-related, and DNA-dependent PKs (4,5).…”

mentioning

confidence: 99%

See 1 more Smart Citation

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

Abu-Odeh

Salah

Herbel

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

122

View full text Add to dashboard Cite

Genomic instability is a hallmark of cancer. The WW domaincontaining oxidoreductase (WWOX) is a tumor suppressor spanning the common chromosomal fragile site FRA16D. Here, we report a direct role of WWOX in DNA damage response (DDR) and DNA repair. We show that Wwox deficiency results in reduced activation of the ataxia telangiectasia-mutated (ATM) checkpoint kinase, inefficient induction and maintenance of γ-H2AX foci, and impaired DNA repair. Mechanistically, we show that, upon DNA damage, WWOX accumulates in the cell nucleus, where it interacts with ATM and enhances its activation. Nuclear accumulation of WWOX is regulated by its K63-linked ubiquitination at lysine residue 274, which is mediated by the E3 ubiquitin ligase ITCH. These findings identify a novel role for the tumor suppressor WWOX and show that loss of WWOX expression may drive genomic instability and provide an advantage for clonal expansion of neoplastic cells.genomic instability | common fragile sites | WW domain-containing oxidoreductase | ataxia telangiectasia-mutated | ITCH G enomic instability is a common characteristic of human cancers. The DNA damage response (DDR) maintains the integrity of the genome in response to DNA damage. DDR is a complex signaling process that results in cell cycle arrest followed by either DNA repair or apoptosis if the DNA damage is too extensive to be repaired (1-3). Key mammalian damage response sensors are ataxia telangiectasia-mutated (ATM), ATM and Rad3-related, and DNA-dependent PKs (4, 5). Disruption of the DDR machinery in human cells leads to genomic instability and an increased risk of cancer progression (6, 7).The WW domain-containing oxidoreductase (WWOX) gene spans the common fragile site (CFS) FRA16D (8, 9). Genomic alterations affecting the WWOX locus have been reported in several types of cancer and include homozygous and hemizygous deletions (10-13). Ectopic expression of WWOX in WWOXnegative cancer cells attenuates cell growth and suppresses tumor growth in immunocompromised mice (10,11,14). Importantly, targeted ablation of Wwox in mice results in higher incidence of spontaneous lesions resembling osteosarcomas and lung and mammary tumors (14-16). These findings suggest WWOX as a tumor suppressor. The WWOX protein contains two Nterminal WW domains mediating WWOX interaction with PP(proline)x(amino acid)Y(tyrosine)-containing proteins (11, 17) and a central short-chain deyhdrogenase/reductase domain that has been proposed to function in steroidogenesis (18). Recent characterization of WWOX domains revealed that they interact, mainly through the WW1 domain, with multiprotein networks (3). The mechanism by which WWOX suppresses tumorigenicity is, however, not well-known.In vitro, CFSs are defined as gaps or breaks on metaphase chromosomes that occur in cells treated with inhibitors of DNA replication (19,20). In vivo, CFSs are preferential targets of replication stress in preneoplastic lesions (21), and emerging evidence suggests that they represent early warning sensors for DNA damage (22-24). ...

show abstract

Characterizing WW Domain Interactions of Tumor Suppressor WWOX Reveals Its Association with Multiprotein Networks

Cited by 84 publications

References 67 publications

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

The Tumor-Suppressor WWOX and HDAC3 Inhibit the Transcriptional Activity of the β-Catenin Coactivator BCL9-2 in Breast Cancer Cells

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

Contact Info

Product

Resources

About