PKA-mediated protein phosphorylation regulates ezrin–WWOX interaction

Jin, Changjie; Ge, Ling; Ding, Xia; Chen, Yong; Zhu, Hongling; Ward, Tarsha; Wu, Fang; Cao, Xinwang; Wang, Qichen; Yao, Xuebiao

doi:10.1016/j.bbrc.2006.01.023

Cited by 57 publications

(55 citation statements)

References 21 publications

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“…It is regulated by integrin signaling and promotes cell motility via Cdc42 (47), and it has recently been shown to phosphorylate WWOX protein and target it for proteasomal degradation (48). Ezrin is a cytoplasmic protein linking transmembrane signaling to cytoskeletal reorganization and can bind WWOX to the cytoskeleton during differentiation of gastric parietal cells (49). Ezrin has also been shown to decrease cell-ECM adhesion, motility, and invasion in colorectal cancer cells (50).…”

Section: Discussionmentioning

confidence: 99%

WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

et al. 2009

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The WW domain-containing oxidoreductase (WWOX) gene is located at FRA16D, a common fragile site involved in human cancer. Targeted deletion of Wwox in mice causes increased spontaneous tumor incidence, confirming that WWOX is a bona fide tumor suppressor gene. We show that stable transfection of WWOX into human PEO1 ovarian cancer cells, containing homozygous WWOX deletion, abolishes in vivo tumorigenicity, but this does not correlate with alteration of in vitro growth. Rather, WWOX restoration in PEO1, or WWOX overexpression in SKOV3 ovarian cancer cells, results in reduced attachment and migration on fibronectin, an extracellular matrix component linked to peritoneal metastasis. Conversely, siRNA-mediated knockdown of endogenous WWOX in A2780 ovarian cancer cells increases adhesion to fibronectin. In addition, whereas there is no WWOX-dependent difference in cell death in adherent cells, WWOXtransfected cells in suspension culture display a proapoptotic phenotype. We further show that WWOX expression reduces membranous integrin A 3 protein but not integrin A 3 mRNA levels, and that adhesion of PEO1 cells to fibronectin is predominantly mediated through integrin A 3 . We therefore propose that WWOX acts as an ovarian tumor suppressor by modulating the interaction between tumor cells and the extracellular matrix and by inducing apoptosis in detached cells. Consistent with this, the suppression of PEO1 tumorigenicity by WWOX can be partially overcome by implanting these tumor cells in Matrigel. These data suggest a possible role for the loss of WWOX in the peritoneal dissemination of human ovarian cancer cells. [Cancer Res 2009;69(11):4835-42]

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Section: Discussionmentioning

confidence: 99%

WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

et al. 2009

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“…In sharp contrast to the positive staining pattern of parietal cells, the tall columnar mucus secreting epithelial cells from the surface and pit were consistently negative for WWOX expression. Interestingly, a recent report by (Jin et al 2006) presented evidence that ezrin is one of the many potential WWOX's interacting partners. These authors described that the ezrin-WWOX interaction takes place at the apical membrane of gastric parietal cells and that this interaction appears regulated by Protein Kinase A via phosphorylation of ezrin's Ser 66.…”

Section: Wwox Expression In the Digestive Tract And Accessory Glandsmentioning

confidence: 99%

“…These authors described that the ezrin-WWOX interaction takes place at the apical membrane of gastric parietal cells and that this interaction appears regulated by Protein Kinase A via phosphorylation of ezrin's Ser 66. Ezrin is known to be a protein implicated in cell shape, adhesion, motility, survival (Bretscher et al 2002) and apical polarity in epithelial cells (Jin et al 2006) demonstrated that WWOX, H-K-ATPase and ezrin biochemically interact and co-localize to the apical membrane of parietal cells. These observations are consistent with our findings of WWOX being predominantly expressed in epithelial secretory cell types.…”

Section: Wwox Expression In the Digestive Tract And Accessory Glandsmentioning

confidence: 99%

WWOX protein expression in normal human tissues

2006

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WWOX is a putative tumor suppressor gene that spans approximately a 1 Mb genomic region and is the site for the second most common chromosomal fragile site, FRA16D at 16q23. Various studies have focused on the expression of WWOX in human cancer mostly at the RNA level, but little is known about the normal pattern of WWOX protein expression in nonneoplastic tissues. In this study, a comprehensive analysis of WWOX protein expression in normal tissues was performed by means of immunohistochemistry utilizing a very specific anti-WWOX polyclonal antibody. We analyzed tissue cores of human samples representing more than 30 organs, using various tissue microarray (TMA) slides. Due to the potential role of WWOX in sex-steroid metabolism, whole sections from hormonally regulated organs like breast, ovaries, testes and prostate were also analyzed. The results from our study indicate that WWOX is preferentially highly expressed in secretory epithelial cells of reproductive, endocrine and exocrine organs, as well as in ductal epithelial cells from specific segments of the urinary system. Interestingly, we also observed significant WWOX protein expression in various cell types of neural origin including neurons, ependymal cells and astrocytes. No expression of WWOX was detected in adipose, connective, and lymphoid tissues, myelinized structures and blood vessels. By better defining the topographic distribution of WWOX in normal tissues this study provides some insight on the potential physiological role of this novel protein.

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“…WWOX physically associates with c-Jun following ultraviolet radiation and functionally suppresses its transcriptional ability (12). Other research groups have shown that WWOX associates with proline-rich motifs of SIMPLE (13) and EZRIN (14) and with proteins lacking the PPXY motif such as p53 and c-Jun N-terminal kinase (JNK) (15). Thus, although WWOX is involved in specific protein complexes that define its function as an important suppressor of transactivator functions, its specific function in vivo is not clearly defined.…”

mentioning

confidence: 99%

The WWOX Tumor Suppressor Is Essential for Postnatal Survival and Normal Bone Metabolism

Aqeilan

Hassan

Bruin

et al. 2008

Journal of Biological Chemistry

120

177

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The WW domain-containing oxidoreductase (WWOX) gene encodes a tumor suppressor. We have previously shown that targeted ablation of the Wwox gene in mouse increases the incidence of spontaneous and chemically induced tumors. To investigate WWOX function in vivo, we examined Wwox-deficient (Wwox ؊/؊ ) mice for phenotypical abnormalities. Wwox ؊/؊ mice are significantly reduced in size, die at the age of 2-3 weeks, and suffer a metabolic disorder that affects the skeleton. Wwox ؊/؊ mice exhibit a delay in bone formation from a cell autonomous defect in differentiation beginning at the mineralization stage shown in calvarial osteoblasts ex vivo and supported by significantly decreased bone formation parameters in Wwox ؊/؊ mice by microcomputed tomography analyses. Wwox ؊/؊ mice develop metabolic bone disease, as a consequence of reduced serum calcium, hypoproteinuria, and hypoglycemia leading to increased osteoclast activity and bone resorption. Interestingly, we find WWOX physically associates with RUNX2, the principal transcriptional regulator of osteoblast differentiation, and on osteocalcin chromatin. We show WWOX functionally suppresses RUNX2 transactivation ability in osteoblasts. In breast cancer MDA-MB-242 cells that lack endogenous WWOX protein, restoration of WWOX expression inhibited Runx2 and RUNX2 target genes related to metastasis. Affymetrix mRNA profiling revealed common gene targets in multiple tissues. In Wwox ؊/؊ mice, genes related to nucleosome assembly and cell growth genes were down-regulated, and negative regulators of skeletal metabolism exhibited increased expression. Our results demonstrate an essential requirement for the WWOX tumor suppressor in postnatal survival, growth, and metabolism and suggest a central role for WWOX in regulation of bone tissue formation. WW domain-containing oxidoreductase (WWOX)3 is a 46-kDa protein that contains two N-terminal WW domains and a central short-chain dehydrogenase/reductase domain (1, 2). WWOX was identified as a putative tumor suppressor in cancer cells because it lies in a genomic region that is frequently altered in pre-neoplastic and neoplastic lesions (1, 2). Indeed, expression of WWOX is deregulated in several types of cancer, including breast, prostate, lung, stomach, and pancreatic carcinomas (3, 4). Ectopic expression of WWOX in cancer cells lacking expression of endogenous WWOX results in significant growth inhibition and prevents the development of tumors in athymic nude mice (5, 6). Recently, we generated a mouse carrying a targeted deletion of the Wwox gene (7). We reported that loss of both alleles of Wwox resulted in the formation of frequent juvenile osteosarcomas, whereas loss of one allele increased the incidence of spontaneous and chemically induced tumors (7, 8) thus confirming that Wwox is a bona fide tumor suppressor.The identification of WWOX-interacting proteins has provided insights into the potential roles of WWOX in cell signaling and its impact on cell fate. WWOX cytosolic interactions, through its first WW domain that b...

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PKA-mediated protein phosphorylation regulates ezrin–WWOX interaction

Cited by 57 publications

References 21 publications

WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3

WWOX protein expression in normal human tissues

The WWOX Tumor Suppressor Is Essential for Postnatal Survival and Normal Bone Metabolism

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