Molecular Origin of the Binding of WWOX Tumor Suppressor to ErbB4 Receptor Tyrosine Kinase

Schuchardt, Brett J.; Bhat, Vikas; Mikles, David C.; McDonald, Caleb B.; Sudol, Marius; Farooq, Amjad

doi:10.1021/bi400987k

Cited by 24 publications

(52 citation statements)

References 85 publications

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“…Furthermore, the Y85W substitution within the WW2 domain restores its binding to PPXY motifs of ErbB4 in a manner very similar to the binding of the WW1 domain of WWOX. Altogether, these data indicate that WW1 domain is the predominant interacting module of WWOX and that the WW2 atypical nature explains its failure to mediate protein-protein interaction (60). Future analysis shall further decipher the significance of WW2 domain of WWOX for its interacting ability.…”

Section: Discussionmentioning

confidence: 83%

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

Abu-Odeh

Bar-Mag

Huang

et al. 2014

Journal of Biological Chemistry

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121

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Background: WWOX encodes a 46-kDa tumor suppressor. Results: WW1 domain of WWOX mediates its protein-protein interaction with PY motifs that are involved in molecular processes, including transcription, RNA processing, and metabolism. Conclusion: The WW1 domain of WWOX provides a versatile platform that links WWOX with individual proteins associated with physiologically important networks. Significance: This study provides a better understanding of WWOX biology in normal and disease states.

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Section: Discussionmentioning

confidence: 83%

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

Abu-Odeh

Bar-Mag

Huang

et al. 2014

Journal of Biological Chemistry

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121

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“…The WWOX WW2 is not a classical WW domain due to the replacement of the second signature tryptophan with a tyrosine at position 85. In a recent report that analyzed the interaction between WWOX WW domains and ERBB4-CTF, it was shown that the WW2 domain does not bind to consensus PPxY motifs but does augment the ability of WW1 to do so (64). …”

Section: 1 Wwox In Cellular Pathwaysmentioning

confidence: 99%

WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies

Aldaz

Ferguson

Abba

2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

124

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WWOX was cloned as a putative tumor suppressor gene mapping to chromosomal fragile site FRA16D. Deletions affecting WWOX accompanied by loss of expression are frequent in various epithelial cancers. Translocations and deletions affecting WWOX are also common in multiple myeloma and are associated with worse prognosis. Metanalysis of gene expression datasets demonstrates that low WWOX expression is significantly associated with shorter relapse-free survival in ovarian and breast cancer patients. Although somatic mutations affecting WWOX are not frequent, analysis of TCGA tumor datasets led to identifying 44 novel mutations in various tumor types. The highest frequencies of mutations were found in head and neck cancers, uterine and gastric adenocarcinomas. Mouse models of gene ablation led us to conclude that Wwox does not behave as a highly penetrant, classical tumor suppressor gene since its deletion is not tumorigenic in most models and its role is more likely to be of relevance in tumor progression rather than in initiation. Analysis of signaling pathways associated with WWOX expression confirmed previous in vivo and in vitro observations linking WWOX function with the TGFβ/SMAD and WNT signaling pathways and with specific metabolic processes. Supporting these conclusions recently we demonstrated that indeed WWOX behaves as a modulator of TGFβ/SMAD signaling by binding and sequestering SMAD3 in the cytoplasmic compartment. As a consequence progressive loss of WWOX expression in advanced breast cancer would contribute to the pro-metastatic effects resulting from TGFβ/SMAD3 hyperactive signaling in breast cancer. Recently, GWAS and resequencing studies have linked the WWOX locus with familial dyslipidemias and metabolic syndrome related traits. Indeed, gene expression studies in liver conditional KO mice confirmed an association between WWOX expression and lipid metabolism. Finally, very recently the first human pedigrees with probands carrying homozygous germline loss of function WWOX mutations have been identified. These patients are characterized by severe CNS related pathology that includes epilepsy, ataxia and mental retardation. In summary, WWOX is a highly conserved and tightly regulated gene throughout evolution and when defective or deregulated the consequences are important and deleterious as demonstrated by its association not only with poor prognosis in cancer but also with other important human pathologies such as metabolic syndrome and CNS related pathologic conditions.

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“…Sequence analysis of WW1 and WW2 revealed that the change of a single, highly conserved residue in WW2, Tyr-85, is responsible for WW2's low affinity to the ligand. Indeed, a Y85W mutant is enough to re-establish binding of WW2 to partner PPXY motifs (44). Thus, it has been suggested that the specific mechanism used by WWOX's WW domains is that of a chaperone effect, with WW2 regulating binding of WW1 to its partner, either by stabilizing WW1 and thereby increasing binding affinity (44) or by binding to WW1 in an orientation that occludes the PPXY binding site, generating an internal interaction that can compete with interactions with partners (42,43).…”

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

confidence: 99%

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Abu-Remaileh¹,

Joy-Dodson²,

Schueler‐Furman³

et al. 2015

Journal of Biological Chemistry

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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...

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Molecular Origin of the Binding of WWOX Tumor Suppressor to ErbB4 Receptor Tyrosine Kinase

Cited by 24 publications

References 85 publications

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

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

WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies

Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

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